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Current and emerging treatment options for premature ejaculation

Subjects

Abstract

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.

Key points

  • An increasing number of studies aiming to find an ideal treatment for premature ejaculation are in progress.

  • Currently, most of drug development research for premature ejaculation targets the serotonergic system.

  • Preliminary results of trials with pharmacotherapies targeting other neurotransmitters, such as adrenaline and oxytocin, are promising.

  • Non-pharmacological treatments such as surgical interventions and neuromodulation are gaining popularity; however, additional clinical data are warranted.

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Fig. 1: Neuroanatomical mechanisms of ejaculation.
Fig. 2: Mechanism of action of acute and chronic treatment with selective serotonin reuptake inhibitors.
Fig. 3: Emission phase of ejaculation and mechanism of action of α1 adenoreceptor blockers.
Fig. 4: Central and peripheral effects of oxytocin receptor blockade on ejaculation reflexes of male rats.

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5 5th edn (American Psychiatric Association, 2013).

  2. Parnham, A. & Serefoglu, E. C. Classification and definition of premature ejaculation. Transl. Androl. Urol. 5, 416–423 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Serefoglu, E. C. et al. An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. J. Sex. Med. 11, 1423–1441 (2014).

    Article  PubMed  Google Scholar 

  4. Waldinger, M. D. & Schweitzer, D. H. Changing paradigms from a historical DSM-III and DSM-IV view toward an evidence-based definition of premature ejaculation. Part II — proposals for DSM-V and ICD-11. J. Sex. Med. 3, 693–705 (2006).

    Article  PubMed  Google Scholar 

  5. Serefoglu, E. C. et al. 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. J. Sex. Med. 8, 1177–1185 (2011).

    Article  PubMed  Google Scholar 

  6. Serefoglu, E. C., Cimen, H. I., Atmaca, A. F. & Balbay, M. D. The distribution of patients who seek treatment for the complaint of ejaculating prematurely according to the four premature ejaculation syndromes. J. Sex. Med. 7, 810–815 (2010).

    Article  PubMed  Google Scholar 

  7. Serefoglu, E. C. et al. Prevalence of the complaint of ejaculating prematurely and the four premature ejaculation syndromes: results from the Turkish Society of Andrology Sexual Health Survey. J. Sex. Med. 8, 540–548 (2011).

    Article  PubMed  Google Scholar 

  8. Porst, H. et al. The premature ejaculation prevalence and attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur. Urol. 51, 816–823 (2007).

    Article  PubMed  Google Scholar 

  9. Laumann, E. O., Paik, A. & Rosen, R. C. Sexual dysfunction in the United States: prevalence and predictors. JAMA 281, 537–544 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Tang, W. S. & Khoo, E. M. Prevalence and correlates of premature ejaculation in a primary care setting: a preliminary cross-sectional study. J. Sex. Med. 8, 2071–2078 (2011).

    Article  PubMed  Google Scholar 

  11. McMahon, C. G., Lee, G., Park, J. K. & Adaikan, P. G. Premature ejaculation and erectile dysfunction prevalence and attitudes in the Asia-Pacific region. J. Sex. Med. 9, 454–465 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Saitz, T. R. & Serefoglu, E. C. The epidemiology of premature ejaculation. Transl. Androl. Urol. 5, 409–415 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Althof, S. E. et al. An update of the International Society of Sexual Medicine’s Guidelines for the diagnosis and treatment of premature ejaculation (PE). Sex. Med. 2, 60–90 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Waldinger, M. D. et al. A multinational population survey of intravaginal ejaculation latency time. J. Sex. Med. 2, 492–497 (2005).

    Article  PubMed  Google Scholar 

  15. Waldinger, M. D., McIntosh, J. & Schweitzer, D. H. A five-nation survey to assess the distribution of the intravaginal ejaculatory latency time among the general male population. J. Sex. Med. 6, 2888–2895 (2009).

    Article  PubMed  Google Scholar 

  16. Kempeneers, P. et al. Functional and psychological characteristics of Belgian men with premature ejaculation and their partners. Arch. Sex. Behav. 42, 51–66 (2013).

    Article  PubMed  Google Scholar 

  17. Gopalakrishna, A. et al. Characteristics of men who are bothered by rapid ejaculation: results from clinical intake surveys. Int. J. Impot. Res. 33, 369–375 (2021).

    Article  PubMed  Google Scholar 

  18. Saitz, T. R. & Serefoglu, E. C. Advances in understanding and treating premature ejaculation. Nat. Rev. Urol. 12, 629–640 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Culha, M. G., Tuken, M., Gonultas, S., Cakir, O. O. & Serefoglu, E. C. Frequency of etiological factors among patients with acquired premature ejaculation: prospective, observational, single-center study. Int. J. Impot. Res. https://doi.org/10.1038/s41443-019-0188-x (2019).

    Article  PubMed  Google Scholar 

  20. McMahon, C. G., Jannini, E. A., Serefoglu, E. C. & Hellstrom, W. J. The pathophysiology of acquired premature ejaculation. Transl. Androl. Urol. 5, 434–449 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Waldinger, M. D. The pathophysiology of lifelong premature ejaculation. Transl. Androl. Urol. 5, 424–433 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Donatucci, C. F. Etiology of ejaculation and pathophysiology of premature ejaculation. J. Sex. Med. 3, 303–308 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Guo, L. et al. Significance of penile hypersensitivity in premature ejaculation. Sci. Rep. 7, 10441 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Corona, G. et al. Interplay between premature ejaculation and erectile dysfunction: a systematic review and meta-analysis. J. Sex. Med. 12, 2291–2300 (2015).

    Article  PubMed  Google Scholar 

  25. Fu, X. et al. Association between lifelong premature ejaculation and polymorphism of tryptophan hydroxylase 2 gene in the Han population. Sex. Med. 8, 223–229 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Janssen, P. K., Schaik, R., Olivier, B. & Waldinger, M. D. The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. Asian J. Androl. 16, 607–610 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Salem, A. M., Kamel, I. I., Rashed, L. A. & GamalEl Din, S. F. Effects of paroxetine on intravaginal ejaculatory latency time in Egyptian patients with lifelong premature ejaculation as a function of serotonin transporter polymorphism. Int. J. Impot. Res. 29, 7–11 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Eltonsi, T. K., Tawfik, T. M., Rashed, L. A., GamalEl Din, S. F. & Mahmoud, M. A. Study of the link between dopamine transporter gene polymorphisms and response to paroxetin and escitalopram in patients with lifelong premature ejaculation. Int. J. Impot. Res. 29, 235–239 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Abu El-Hamd, M. & Farah, A. Possible role of serum testosterone, gonadotropins and prolactin in patients with premature ejaculation. Andrologia https://doi.org/10.1111/and.12808 (2018).

    Article  PubMed  Google Scholar 

  30. Cihan, A. et al. The relationship between premature ejaculation and hyperthyroidism. J. Urol. 181, 1273–1280 (2009).

    Article  PubMed  Google Scholar 

  31. Sihotang, R. C. et al. Premature ejaculation in patients with lower urinary tract symptoms: a systematic review. Int. J. Impot. Res. 33, 516–524 (2021).

    Article  PubMed  Google Scholar 

  32. Shamloul, R. & el-Nashaar, A. Chronic prostatitis in premature ejaculation: a cohort study in 153 men. J. Sex. Med. 3, 150–154 (2006).

    Article  PubMed  Google Scholar 

  33. Waldinger, M. D., Zwinderman, A. H., Schweitzer, D. H. & Olivier, B. Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis. Int. J. Impot. Res. 16, 369–381 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Waldinger, M. D. Towards evidence-based drug treatment research on premature ejaculation: a critical evaluation of methodology. Int. J. Impot. Res. 15, 309–313 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. McMahon, C. G. & Porst, H. Oral agents for the treatment of premature ejaculation: review of efficacy and safety in the context of the recent International Society for Sexual Medicine criteria for lifelong premature ejaculation. J. Sex. Med. 8, 2707–2725 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Xia, J.-D., Han, Y.-F., Zhou, L.-H., Chen, Y. & Dai, Y.-T. Efficacy and safety of local anaesthetics for premature ejaculation: a systematic review and meta-analysis. Asian J. Androl. 15, 497–502 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Salonia, A. et al. Acceptance of and discontinuation rate from paroxetine treatment in patients with lifelong premature ejaculation. J. Sex. Med. 6, 2868–2877 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Boeri, L., Pozzi, E., Fallara, G., Montorsi, F. & Salonia, A. Real-life use of the eutectic mixture lidocaine/prilocaine spray in men with premature ejaculation. Int. J. Impot. Res. https://doi.org/10.1038/s41443-021-00424-9 (2021).

    Article  PubMed  Google Scholar 

  39. Abu El-Hamd, M. Effectiveness and tolerability of lidocaine 5% spray in the treatment of lifelong premature ejaculation patients: a randomized single-blind placebo-controlled clinical trial. Int. J. Impot. Res. 33, 96–101 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Mondaini, N. et al. Dapoxetine treatment in patients with lifelong premature ejaculation: the reasons of a “Waterloo”. Urology 82, 620–624 (2013).

    Article  PubMed  Google Scholar 

  41. Clement, P. & Giuliano, F. Physiology and pharmacology of ejaculation. Basic. Clin. Pharmacol. Toxicol. 119 (Suppl. 3), 18–25 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Giuliano, F. & Clement, P. Neuroanatomy and physiology of ejaculation. Annu. Rev. Sex. Res. 16, 190–216 (2005).

    PubMed  Google Scholar 

  43. Truitt, W. A. & Coolen, L. M. Identification of a potential ejaculation generator in the spinal cord. Science 297, 1566–1569 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Veening, J. & Coolen, L. Neural mechanisms of sexual behavior in the male rat: emphasis on ejaculation-related circuits. Pharmacol. Biochem. Behav. 121, 170–183 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Levin, R. J. The mechanisms of human ejaculation — a critical analysis. Sex. Relatsh. Ther. 20, 123–131 (2005).

    Article  Google Scholar 

  46. Alwaal, A., Breyer, B. N. & Lue, T. F. Normal male sexual function: emphasis on orgasm and ejaculation. Fertil. Steril. 104, 1051–1060 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. McMahon, C. G. et al. Disorders of orgasm and ejaculation in men. J. Sex. Med. 1, 58–65 (2004).

    Article  PubMed  Google Scholar 

  48. Missale, C., Nash, S. R., Robinson, S. W., Jaber, M. & Caron, M. G. Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Neve, K. A. & Neve, R. L. in The Dopamine Receptors 27–76 (Springer, 1997).

  50. Neve, K. A., Seamans, J. K. & Trantham-Davidson, H. Dopamine receptor signaling. J. Recept. Signal Transduct. Res. 24, 165–205 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Paglietti, E., Quarantotti, B. P., Mereu, G. & Gessa, G. Apomorphine and L-DOPA lower ejaculation threshold in the male rat. Physiol. Behav. 20, 559–562 (1978).

    Article  CAS  PubMed  Google Scholar 

  52. Pfaus, J. G. & Phillips, A. G. Role of dopamine in anticipatory and consummatory aspects of sexual behavior in the male rat. Behav. Neurosci. 105, 727 (1991).

    Article  CAS  PubMed  Google Scholar 

  53. Berger, M., Gray, J. A. & Roth, B. L. The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Barnes, N. M. et al. International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacol. Rev. 73, 310–520 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Giuliano, F. & Clément, P. Physiology of ejaculation: emphasis on serotonergic control. Eur. Urol. 48, 408–417 (2005).

    Article  PubMed  Google Scholar 

  56. Barnes, N. M. & Sharp, T. A review of central 5-HT receptors and their function. Neuropharmacology 38, 1083–1152 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Hillegaart, V. & Ahlenius, S. Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. Br. J. Pharmacol. 125, 1733–1743 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Garcia-Garcia, A. L., Newman-Tancredi, A. & Leonardo, E. D. 5-HT1A [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. Psychopharmacology 231, 623–636 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Esquivel-Franco, D. C., de Boer, S. F., Waldinger, M., Olivier, B. & Olivier, J. D. A. Pharmacological studies on the role of 5-HT1A receptors in male sexual behavior of wildtype and serotonin transporter knockout rats. Front. Behav. Neurosci. 14, 40 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Waldinger, M. D. The neurobiological approach to premature ejaculation. J. Urol. 168, 2359–2367 (2002).

    Article  PubMed  Google Scholar 

  61. Lasker, G. F., Halis, F. & Gokce, A. Selective serotonin reuptake inhibitors for premature ejaculation: review of erectile and ejaculatory side effects. Curr. Drug Saf. 9, 118–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Waldinger, M. D., Rietschel, M., Nöthen, M. M., Hengeveld, M. W. & Olivier, B. Familial occurrence of primary premature ejaculation. Psychiatr. Genet. 8, 37 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Jern, P. et al. Premature and delayed ejaculation: genetic and environmental effects in a population-based sample of Finnish twins. J. Sex. Med. 4, 1739–1749 (2007).

    Article  PubMed  Google Scholar 

  64. Janssen, P. K. et al. Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation. J. Sex. Med. 6, 276–284 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Janssen, P. K., van Schaik, R., Zwinderman, A. H., Olivier, B. & Waldinger, M. D. The 5-HT1A receptor C(1019)G polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. Pharmacol. Biochem. Behav. 121, 184–188 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Waldinger, M. D. Ejaculatio praecox, erectio praecox, and detumescentia praecox as symptoms of a hypertonic state in lifelong premature ejaculation: a new hypothesis. Pharmacol. Biochem. Behav. 121, 189–194 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Ehrentheil, O. F. A case of premature ejaculation in Greek mythology. J. Sex. Res. 10, 128–131 (1974).

    Article  Google Scholar 

  68. Abraham, K. Über ejaculatio praecox. Int. Z. Psychoanal. 4, 171–186 (1917).

    Google Scholar 

  69. Gross, S. W. & History of Medicine Collections (Duke University). A Practical Treatise on Impotence, Sterility, and Allied Disorders of the Male Sexual Organs (H.C. Lea’s Son, 1881).

  70. Waldinger, M. D. The need for a revival of psychoanalytic investigations into premature ejaculation. J. Mens Health Gend. 3, 390–396 (2006).

    Article  Google Scholar 

  71. Schapiro, B. Premature ejaculation: a review of 1130 cases. J. Urol. 50, 374–379 (1943).

    Article  Google Scholar 

  72. Aycock, L. The medical management of premature ejaculation. J. Urol. 62, 361–361 (1949).

    Article  CAS  PubMed  Google Scholar 

  73. Singh, H. A case of inhibition of ejaculation as a side effect of Mellaril. Am. J. Psychiatry 117, 1041–1042 (1961).

    Article  Google Scholar 

  74. Freyhan, F. A. Loss of ejaculation during Mellaril treatment. Am. J. Psychiatry 118, 171–172 (1961).

    Article  CAS  PubMed  Google Scholar 

  75. Mellgren, A. Treatment of ejaculatio praecox with thioridazine. Psychother. Psychosom. 15, 454–460 (1967).

    Article  Google Scholar 

  76. Bennett, D. Treatment of ejaculatio praecox with monoamine-oxidase inhibitors. Lancet 278, 1309 (1961).

    Article  Google Scholar 

  77. Rapp, M. S. Two cases of ejaculatory impairment related to phenelzine. Am. J. Psychiatry 136, 1200–1201 (1979).

    Article  CAS  PubMed  Google Scholar 

  78. Semans, J. H. Premature ejaculation: a new approach. South. Med. J. 49, 353–358 (1956).

    Article  CAS  PubMed  Google Scholar 

  79. Masters, W. & Johnson, V. Premature ejaculation. Human Sexual Inadequacy (Little, Brown, 92–115 (1970).

  80. Salonia, A. et al. European Association of Urology guidelines on sexual and reproductive health — 2021 update: male sexual dysfunction. Eur. Urol. https://doi.org/10.1016/j.eururo.2021.06.007 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Eaton, H. Clomipramine (Anafranil) in the treatment of premature ejaculation. J. Int. Med. Res. 1, 432–434 (1973).

    Article  Google Scholar 

  82. Choi, J. B. et al. Efficacy and safety of on demand clomipramine for the treatment of premature ejaculation: a multicenter, randomized, double-blind, phase III clinical trial. J. Urol. 201, 147–152 (2019).

    Article  PubMed  Google Scholar 

  83. Kim, S. W. et al. Tolerability and adequate therapeutic dosage of oral clomipramine for the treatment of premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose, parallel-grouped clinical study. Int. J. Impot. Res. 30, 65–70 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Shilon, M., Paz, G. F. & Homonnai, Z. T. The use of phenoxybenzamine treatment in premature ejaculation. Fertil. Steril. 42, 659–661 (1984).

    Article  CAS  PubMed  Google Scholar 

  85. Homonnai, Z. T., Shilon, M. & Paz, G. F. Phenoxybenzamine — an effective male contraceptive pill. Contraception 29, 479–491 (1984).

    Article  CAS  PubMed  Google Scholar 

  86. National Toxicology Program. Phenoxybenzamine hydrochloride. Rep. Carcinog. 12, 344–345 (2011).

    Google Scholar 

  87. Lowe, F. C. Role of the newer alpha, -adrenergic-receptor antagonists in the treatment of benign prostatic hyperplasia-related lower urinary tract symptoms. Clin. Ther. 26, 1701–1713 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Akin, Y., Gulmez, H., Ates, M., Bozkurt, A. & Nuhoglu, B. Comparison of alpha blockers in treatment of premature ejaculation: a pilot clinical trial. Iran. Red. Crescent Med. J. 15, e13805 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Yoon, S. et al. Phenoxybenzamine hydrochloride: Summary Report (University of Maryland Baltimore, 2020).

  90. Waldinger, M. D., Hengeveld, M. W. & Zwinderman, A. H. Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study. Am. J. Psychiatry 151, 1377–1379 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Mendels, J., Camera, A. & Sikes, C. Sertraline treatment for premature ejaculation. J. Clin. Psychopharmacol. 15, 341–346 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Kara, H. et al. The efficacy of fluoxetine in the treatment of premature ejaculation: a double-blind placebo controlled study. J. Urol. 156, 1631–1632 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Ludovico, G. M. et al. Paroxetine in the treatment of premature ejaculation. Br. J. Urol. 77, 881–882 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Kim, S. C. & Seo, K. K. Efficacy and safety of fluoxetine, sertraline and clomipramine in patients with premature ejaculation: a double-blind, placebo controlled study. J. Urol. 159, 425–427 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Waldinger, M., Hengeveld, M. & Zwinderman, A. Ejaculation-retarding properties of paroxetine in patients with primary premature ejaculation: a double-blind, randomized, dose-response study. Br. J. Urol. 79, 592–595 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. McMahon, C. & Touma, K. Treatment of premature ejaculation with paroxetine hydrochloride. Int. J. Impot. Res. 11, 241–246 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Waldinger, M. D., Zwinderman, A. H. & Olivier, B. Antidepressants and ejaculation: a double-blind, randomized, placebo-controlled, fixed-dose study with paroxetine, sertraline, and nefazodone. J. Clin. Psychopharmacol. 21, 293–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Waldinger, M. D., Zwinderman, A. H. & Olivier, B. Antidepressants and ejaculation: a double-blind, randomized, fixed-dose study with mirtazapine and paroxetine. J. Clin. Psychopharmacol. 23, 467–470 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Wang, W.-f, Chang, L., Minhas, S. & Ralph, D. J. Selective serotonin reuptake inhibitors in the treatment of premature ejaculation. Chin. Med. J. 120, 1000–1006 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Waldinger, M. D., Berendsen, H. H. G., Blok, B. F. M., Olivier, B. & Holstege, G. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system. Behav. Brain Res. 92, 111–118 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Hamilton, C. L. & Cornpropst, J. D. Determination of dapoxetine, an investigational agent with the potential for treating depression, and its mono- and di-desmethyl metabolites in human plasma using column-switching high-performance liquid chromatography. J. Chromatogr. 612, 253–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  102. Pryor, J. L. et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet 368, 929–937 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. McMahon, C. G. et al. Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials. J. Sex. Med. 8, 524–539 (2011).

    Article  PubMed  Google Scholar 

  104. Lue, T. F. et al. Summary of the recommendations on sexual dysfunctions in men. J. Sex. Med. 1, 6–23 (2004).

    Article  PubMed  Google Scholar 

  105. Chierigo, F. et al. Lower urinary tract symptoms and depressive symptoms among patients presenting for distressing early ejaculation. Int. J. Impot. Res. 32, 207–212 (2020).

    Article  PubMed  Google Scholar 

  106. Qin, Z. et al. Safety and efficacy characteristics of oral drugs in patients with premature ejaculation: a Bayesian network meta-analysis of randomized controlled trials. Int. J. Impot. Res. 31, 356–368 (2019).

    Article  CAS  PubMed  Google Scholar 

  107. Salonia, A. et al. in European Association of Urology Guidelines: Sexual and Reproductive Health 2020 Edition Presented at the EAU Annual Congress 2020 (European Association of Urology Guidelines Office, 2020).

  108. Sridharan, K., Sivaramakrishnan, G., Sequeira, R. P. & Al-Khaja, K. A. Pharmacological interventions for premature ejaculation: a mixed-treatment comparison network meta-analysis of randomized clinical trials. Int. J. Impot. Res. 30, 215–223 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Russo, G. I. & Cocci, A. Do we have put a new cornerstone for the treatment of premature ejaculation. Int. J. Impot. Res. 30, 272–273 (2018).

    Article  PubMed  Google Scholar 

  110. Shechter, A., Lowenstein, L., Serefoglu, E. C. & Reisman, Y. Attitudes of sexual medicine specialists toward premature ejaculation diagnosis and therapy. Sex. Med. 4, e209–e216 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Towe, M. et al. “Doc, if it were you, what would you do?”: a survey of Men’s Health specialists’ personal preferences regarding treatment modalities. Int. J. Impot. Res. 33, 303–310 (2021).

    Article  PubMed  Google Scholar 

  112. Moudi, E. & Kasaeeyan, A. A. Comparison between tadalafil plus paroxetine and paroxetine alone in the treatment of premature ejaculation. Nephrourol. Mon. 8, e32286 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Gameel, T. A. et al. On-demand use of tramadol, sildenafil, paroxetine and local anaesthetics for the management of premature ejaculation: a randomised placebo-controlled clinical trial. Arab. J. Urol. 11, 392–397 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Safarinejad, M. R. Comparison of dapoxetine versus paroxetine in patients with premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study. Clin. Neuropharmacol. 29, 243–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Waldinger, M. D., Schweitzer, D. H. & Olivier, B. On-demand SSRI treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions. J. Sex. Med. 2, 121–131 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Waldinger, M. D. Premature ejaculation: definition and drug treatment. Drugs 67, 547–568 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. McMahon, C. G. & Touma, K. Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. J. Urol. 161, 1826–1830 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Waldinger, M. D., Zwinderman, A. H. & Olivier, B. On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment. Eur. Urol. 46, 510–515 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Kim, S. W. & Paick, J. S. Short-term analysis of the effects of as needed use of sertraline at 5 PM for the treatment of premature ejaculation. Urology 54, 544–547 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Modi, N. B. et al. Single-and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation. J. Clin. Pharmacol. 46, 301–309 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Andersson, K. E., Mulhall, J. P. & Wyllie, M. G. Pharmacokinetic and pharmacodynamic features of dapoxetine, a novel drug for ‘on-demand’ treatment of premature ejaculation. BJU Int. 97, 311–315 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Xin, Z. C. et al. Penile sensitivity in patients with primary premature ejaculation. J. Urol. 156, 979–981 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Wyllie, M. G. & Hellstrom, W. J. The link between penile hypersensitivity and premature ejaculation. BJU Int. 107, 452–457 (2011).

    Article  PubMed  Google Scholar 

  124. Berkovitch, M., Keresteci, A. G. & Koren, G. Efficacy of prilocaine-lidocaine cream in treatment of premature ejaculation. J. Urol. 154, 1360–1361 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Busato, W. & Galindo, C. Topical anaesthetic use for treating premature ejaculation: a double-blind, randomized, placebo-controlled study. BJU Int. 93, 1018–1021 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Dinsmore, W. W. et al. Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int. 99, 369–375 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Dinsmore, W. W. & Wyllie, M. G. PSD502 improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study. BJU Int. 103, 940–949 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Carson, C. & 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. J. Sex. Med. 7, 3179–3189 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Martyn-St James, M. et al. Topical anaesthetics for premature ejaculation: a systematic review and meta-analysis. Sex. Health 13, 114–123 (2016).

    Article  PubMed  Google Scholar 

  130. Dresser, M. et al. Pharmacokinetics of single and multiple escalating doses of dapoxetine in healthy volunteers. Clin. Pharmacol. Ther. 75, P32–P32 (2004).

    Article  Google Scholar 

  131. Sangkum, P., Badr, R., Serefoglu, E. C. & Hellstrom, W. J. Dapoxetine and the treatment of premature ejaculation. Transl. Androl. Urol. 2, 301–311 (2013).

    PubMed  PubMed Central  Google Scholar 

  132. Dresser, M. J. et al. Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: Impact of age and effects of a high-fat meal. J. Clin. Pharmacol. 46, 1023–1029 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Buvat, J., Tesfaye, F., Rothman, M., Rivas, D. A. & Giuliano, F. Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries. Eur. Urol. 55, 957–968 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. McMahon, C. G. et al. Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study. J. Sex. Med. 10, 2312–2325 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Tuken, M., Culha, M. G. & Serefoglu, E. C. Efficacy and safety of dapoxetine/sildenafil combination tablets in the treatment of men with premature ejaculation and concomitant erectile dysfunction-DAP-SPEED Study. Int. J. Impot. Res. 31, 92–96 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Cappelleri, J. C., Rosen, R. C., Smith, M. D., Mishra, A. & Osterloh, I. H. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 54, 346–351 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04361305 (2020).

  138. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04703127 (2021).

  139. Yan, W. J., Yu, N., Yin, T. L., Zou, Y. J. & Yang, J. A new potential risk factor in patients with erectile dysfunction and premature ejaculation: folate deficiency. Asian J. Androl. 16, 902–906 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kadihasanoglu, M. et al. Relation between blood vitamin B12 levels with premature ejaculation: case-control study. Andrologia https://doi.org/10.1111/and.12657 (2017).

    Article  PubMed  Google Scholar 

  141. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT04085354 (2019).

  142. Verze, P. et al. Comparison of treatment of emergent adverse events in men with premature ejaculation treated with dapoxetine and alternate oral treatments: results from a large multinational observational trial. J. Sex. Med. 13, 194–199 (2016).

    Article  PubMed  Google Scholar 

  143. Rosen, R. C. et al. Poster 1169: treatment of premature ejaculation (PE) with dapoxetine (DPX) is not associated with suicidality. J. Urol. 177 (Suppl. 4), 385–386 (2007).

    Article  Google Scholar 

  144. Giuliano, F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci. 30, 79–84 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Olivier, B., Van Oorschot, R. & Waldinger, M. Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual behaviour. Int. Clin. Psychopharmacol. 13, S9–S14 (1998).

    Article  PubMed  Google Scholar 

  146. Biri, H. et al. Sertraline in the treatment of premature ejaculation: a double-blind placebo controlled study. Int. Urol. Nephrol. 30, 611–615 (1998).

    Article  CAS  PubMed  Google Scholar 

  147. Mcmahon, C. G. Treatment of premature ejaculation with sertraline hydrochloride: a single-blind placebo controlled crossover study. J. Urol. 159, 1935–1938 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. McMahon, C. Treatment of premature ejaculation with sertraline hydrochloride. Int. J. Impot. Res. 10, 181–184 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Haensel, S., Klem, T., Hop, W. C. & Slob, A. K. Fluoxetine and premature ejaculation: a double-blind, crossover, placebo-controlled study. J. Clin. Psychopharmacol. 18, 72–77 (1998).

    Article  CAS  PubMed  Google Scholar 

  150. Yilmaz, U., Tatlisen, A., Turan, H., Arman, F. & Ekmekcioglu, O. The effects of fluoxetine on several neurophysiological variables in patients with premature ejaculation. J. Urol. 161, 107–111 (1999).

    Article  CAS  PubMed  Google Scholar 

  151. Lee, H. S., Song, D. H., Kim, C.-H. & Choi, H. K. An open clinical trial of fluoxetine in the treatment of premature ejaculation. J. Clin. Psychopharmacol. 16, 379–382 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. Safarinejad, M. & Hosseini, S. Safety and efficacy of citalopram in the treatment of premature ejaculation: a double-blind placebo-controlled, fixed dose, randomized study. Int. J. Impot. Res. 18, 164–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Atmaca, M., Kuloglu, M., Tezcan, E. & Semercioz, A. The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study. Int. J. Impot. Res. 14, 502–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Waldinger, M. D., Hengeveld, M. W., Zwinderman, A. H. & Olivier, B. Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J. Clin. Psychopharmacol. 18, 274–281 (1998).

    Article  CAS  PubMed  Google Scholar 

  155. Fallon, B. ‘Off-label’ drug use in sexual medicine treatment. Int. J. Impot. Res. 20, 127–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. Machado, M., Iskedjian, M., Ruiz, I. & Einarson, T. R. Remission, dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials. Curr. Med. Res. Opin. 22, 1825–1837 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Coupland, N. J., Bell, C. J. & Potokar, J. P. Serotonin reuptake inhibitor withdrawal. J. Clin. Psychopharmacol. 16, 356–362 (1996).

    Article  CAS  PubMed  Google Scholar 

  158. Jern, P., Johansson, A., Piha, J., Westberg, L. & Santtila, P. Antidepressant treatment of premature ejaculation: discontinuation rates and prevalence of side effects for dapoxetine and paroxetine in a naturalistic setting. Int. J. Impot. Res. 27, 75–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  159. Koyuncu, H., Serefoglu, E. C., Ozdemir, A. T. & Hellstrom, W. J. Deleterious effects of selective serotonin reuptake inhibitor treatment on semen parameters in patients with lifelong premature ejaculation. Int. J. Impot. Res. 24, 171–173 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Tanrikut, C. & Schlegel, P. N. Antidepressant-associated changes in semen parameters. Urology 69, 185.e185–185.e187 (2007).

    Article  Google Scholar 

  161. Koyuncu, H. et al. Escitalopram treatment for premature ejaculation has a negative effect on semen parameters. Int. J. Impot. Res. 23, 257–261 (2011).

    Article  CAS  PubMed  Google Scholar 

  162. Akasheh, G., Sirati, L., Noshad Kamran, A. R. & Sepehrmanesh, Z. Comparison of the effect of sertraline with behavioral therapy on semen parameters in men with primary premature ejaculation. Urology 83, 800–804 (2014).

    Article  PubMed  Google Scholar 

  163. Relwani, R. et al. Semen parameters are unrelated to BMI but vary with SSRI use and prior urological surgery. Reprod. Sci. 18, 391–397 (2011).

    Article  PubMed  Google Scholar 

  164. Insel, T. R. et al. Obsessive-compulsive disorder. A double-blind trial of clomipramine and clorgyline. Arch. Gen. Psychiatry 40, 605–612 (1983).

    Article  CAS  PubMed  Google Scholar 

  165. Goodman, R. E. An assessment of clomipramine (Anafranil) in the treatment of premature ejaculation. J. Int. Med. Res. 8 (Suppl. 3), 53–59 (1980).

    PubMed  Google Scholar 

  166. Segraves, R. T., Saran, A., Segraves, K. & Maguire, E. Clomipramine versus placebo in the treatment of premature ejaculation: a pilot study. J. Sex. Marital. Ther. 19, 198–200 (1993).

    Article  CAS  PubMed  Google Scholar 

  167. Strassberg, D. S., de Gouveia Brazao, C. A., Rowland, D. L., Tan, P. & Slob, A. K. Clomipramine in the treatment of rapid (premature) ejaculation. J. Sex. Marital. Ther. 25, 89–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. Wu, P. C., Hung, C. S., Kang, Y. N. & Wu, C. C. Tolerability and optimal therapeutic dosage of clomipramine for premature ejaculation: a systematic review and meta-analysis. Sex. Med. 9, 100283 (2021).

    Article  PubMed  Google Scholar 

  169. Boolell, M. et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int. J. Impot. Res. 8, 47–52 (1996).

    CAS  PubMed  Google Scholar 

  170. Chen, J., Keren-Paz, G., Bar-Yosef, Y. & Matzkin, H. The role of phosphodiesterase type 5 inhibitors in the management of premature ejaculation: a critical analysis of basic science and clinical data. Eur. Urol. 52, 1331–1339 (2007).

    Article  PubMed  Google Scholar 

  171. Krishnappa, P., Fernandez-Pascual, E., Carballido, J. & Martinez-Salamanca, J. I. Sildenafil/Viagra in the treatment of premature ejaculation. Int. J. Impot. Res. 31, 65–70 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Pfaus, J. G. Neurobiology of sexual behavior. Curr. Opin. Neurobiol. 9, 751–758 (1999).

    Article  CAS  PubMed  Google Scholar 

  173. Aversa, A. et al. Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation. Int. J. Impot. Res. 21, 221–227 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. McMahon, C. G. et al. Efficacy of sildenafil citrate (Viagra) in men with premature ejaculation. J. Sex. Med. 2, 368–375 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. Polat, E. C., Ozbek, E., Otunctemur, A., Ozcan, L. & Simsek, A. Combination therapy with selective serotonin reuptake inhibitors and phosphodiesterase-5 inhibitors in the treatment of premature ejaculation. Andrologia 47, 487–492 (2015).

    Article  CAS  PubMed  Google Scholar 

  176. Lee, W. K. et al. Comparison between on-demand dosing of dapoxetine alone and dapoxetine plus mirodenafil in patients with lifelong premature ejaculation: prospective, randomized, double-blind, placebo-controlled, multicenter study. J. Sex. Med. 10, 2832–2841 (2013).

    Article  CAS  PubMed  Google Scholar 

  177. Sun, Y. et al. Efficacy of PDE5Is and SSRIs in men with premature ejaculation: a new systematic review and five meta-analyses. World J. Urol. 35, 1817–1831 (2017).

    Article  CAS  PubMed  Google Scholar 

  178. Dayer, P., Desmeules, J. & Collart, L. [Pharmacology of tramadol]. Drugs 53 (Suppl. 2), 18–24 (1997).

    Article  CAS  PubMed  Google Scholar 

  179. Lee, C. R., McTavish, D. & Sorkin, E. M. Tramadol. Drugs 46, 313–340 (1993).

    Article  CAS  PubMed  Google Scholar 

  180. Safarinejad, M. R. & Hosseini, S. Y. Safety and efficacy of tramadol in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study. J. Clin. Psychopharmacol. 26, 27–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  181. Bar-Or, D., Salottolo, K. M., Orlando, A., Winkler, J. V. & Group, T. O. S. A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes. Eur. Urol. 61, 736–743 (2012).

    Article  CAS  PubMed  Google Scholar 

  182. Salem, E. A. et al. Original research — ejaculatory disorders: tramadol HCL has promise in on-demand use to treat premature ejaculation. J. Sex. Med. 5, 188–193 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Kaynar, M., Kilic, O. & Yurdakul, T. On-demand tramadol hydrochloride use in premature ejaculation treatment. Urology 79, 145–149 (2012).

    Article  PubMed  Google Scholar 

  184. Alghobary, M., El-Bayoumy, Y., Mostafa, Y., Mahmoud, E.-H. M. & Amr, M. Evaluation of tramadol on demand vs. daily paroxetine as a long-term treatment of lifelong premature ejaculation. J. Sex. Med. 7, 2860–2867 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Mittino, D., Mula, M. & Monaco, F. Serotonin syndrome associated with tramadol-sertraline coadministration. Clin. Neuropharmacol. 27, 150–151 (2004).

    Article  PubMed  Google Scholar 

  186. Takeshita, J. & Litzinger, M. H. Serotonin syndrome associated with tramadol. Prim. Care Companion J. Clin. Psychiatry 11, 273 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Kirby, E. W., Carson, C. C. & Coward, R. M. Tramadol for the management of premature ejaculation: a timely systematic review. Int. J. Impot. Res. 27, 121–127 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Waldinger, M. D. Lifelong premature ejaculation: definition, serotonergic neurotransmission and drug treatment. World J. Urol. 23, 102–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Waldinger, M. D. Drug treatment options for premature ejaculation. Expert. Opin. Pharmacother. 19, 1077–1085 (2018).

    Article  CAS  PubMed  Google Scholar 

  190. Park, H. J. et al. Discontinuation of dapoxetine treatment in patients with premature ejaculation: a 2-year prospective observational study. Sex. Med. 5, e99–e105 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Waldinger, M. D. Lifelong premature ejaculation: from authority-based to evidence-based medicine. BJU Int. 93, 201–207 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Rodgers, R. J. & Cooper, S. J. (eds) 5-HT1A Agonists, 5-HT3 Antagonists and Benzodiazepines: Their Comparative Behavioural Pharmacology (Wiley, 1991).

  193. Andersson, G. & Larsson, K. Effects of FG 5893, a new compound with 5-HT1A receptor agonistic and 5-HT2 receptor antagonistic properties, on male rat sexual behavior. Eur. J. Pharmacol. 255, 131–137 (1994).

    Article  CAS  PubMed  Google Scholar 

  194. Haensel, S. M. & Slob, A. K. Flesinoxan: a prosexual drug for male rats. Eur. J. Pharmacol. 330, 1–9 (1997).

    Article  CAS  PubMed  Google Scholar 

  195. Pfaus, J. G. & Heeb, M. M. Implications of immediate-early gene induction in the brain following sexual stimulation of female and male rodents. Brain Res. Bull. 44, 397–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  196. Chéhensse, C. et al. Human spinal ejaculation generator. Ann. Neurol. 81, 35–45 (2017).

    Article  PubMed  Google Scholar 

  197. Waldinger, M. D. & Olivier, B. Animal models of premature and retarded ejaculation. World J. Urol. 23, 115–118 (2005).

    Article  PubMed  Google Scholar 

  198. Jeon, H. J. et al. Candidate molecule for premature ejaculation, DA-8031: in vivo and in vitro characterization of DA-8031. Urology 77, 1006.e1017–1021 (2011).

    Article  Google Scholar 

  199. Kang, K. K. et al. Ejaculatory responses are inhibited by a new chemical entity, DA-8031, in preclinical rodent models of ejaculation. Urology 81, 920.e13–920.e18 (2013).

    Article  Google Scholar 

  200. Kang, K. K., Sung, J. H., Kim, S. H. & Lee, S. Effect of DA-8031, a novel oral compound for premature ejaculation, on male rat sexual behavior. Int. J. Urol. 21, 325–329 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Shin, D. et al. Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects. Drug Des. Dev. Ther. 11, 713 (2017).

    Article  CAS  Google Scholar 

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01798667 (2013).

  203. Lacivita, E. et al. The therapeutic potential of 5-HT1A receptors: a patent review. Expert Opin. Ther. Pat. 22, 887–902 (2012).

    Article  CAS  PubMed  Google Scholar 

  204. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT00664365 (2017).

  205. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT00861484 (2017).

  206. Migliorini, F. et al. A double-blind, placebo-controlled parallel group study to evaluate the effect of a single oral dose of 5-HT1A antagonist GSK958108 on ejaculation latency time in male patients suffering from premature ejaculation. J. Sex. Med. 18, 63–71 (2021).

    Article  CAS  PubMed  Google Scholar 

  207. Migliorini, F. et al. PD28-08 a double-blind, placebo-controlled parallel group study to evaluate the effect of a single oral dose of GSK958108 on ejaculation latency time in male patients suffering from premature ejaculation. J. Urol. 201, e489–e489 (2019).

    Article  Google Scholar 

  208. Marcer, A. et al. A double-blind, placebo-controlled parallel group study to evaluate the effect of a single oral dose of GSK958108 on ejaculation latency time in male patients suffering from premature ejaculation. Eur. Urol. Suppl. 18, e1428 (2019).

    Article  Google Scholar 

  209. Lyons, T. J. & French, J. Modafinil: the unique properties of a new stimulant. Aviat. Space Environ. Med. 62, 432–435 (1991).

    CAS  PubMed  Google Scholar 

  210. Ballon, J. S. & Feifel, D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J. Clin. Psychiatry 67, 554–566 (2006).

    Article  CAS  PubMed  Google Scholar 

  211. Ferraro, L. et al. Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression. J. Neurosci. Res. 68, 107–112 (2002).

    Article  CAS  PubMed  Google Scholar 

  212. Ferraro, L. et al. Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil. Neuropharmacology 39, 1974–1983 (2000).

    Article  CAS  PubMed  Google Scholar 

  213. Regenthal, R., Koch, H., Köhler, C., Preiss, R. & Krügel, U. Depression-like deficits in rats improved by subchronic modafinil. Psychopharmacology 204, 627–639 (2009).

    Article  CAS  PubMed  Google Scholar 

  214. Ferraro, L. et al. Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat. Synapse 55, 230–241 (2005).

    Article  CAS  PubMed  Google Scholar 

  215. Marson, L., Yu, G. & Farber, N. M. The effects of oral administration of d-modafinil on male rat ejaculatory behavior. J. Sex. Med. 7, 70–78 (2010).

    Article  CAS  PubMed  Google Scholar 

  216. Serefoglu, E. C. On-demand d-modafinil may be an effective treatment option for lifelong premature ejaculation: a case report. Andrologia 48, 121–122 (2016).

    Article  CAS  PubMed  Google Scholar 

  217. Tuken, M., Kiremit, M. C. & Serefoglu, E. C. On-demand modafinil improves ejaculation time and patient-reported outcomes in men with lifelong premature ejaculation. Urology 94, 139–142 (2016).

    Article  PubMed  Google Scholar 

  218. Kawabe, K., Yoshida, M., Homma, Y. & Group, S. C. S. Silodosin, a new α1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 98, 1019–1024 (2006).

    Article  CAS  PubMed  Google Scholar 

  219. Roehrborn, C. G., Kaplan, S. A., Lepor, H. & Volinn, W. Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH. Prostate Cancer Prostatic Dis. 14, 143–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  220. Chapple, C. R. et al. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur. Urol. 59, 342–352 (2011).

    Article  CAS  PubMed  Google Scholar 

  221. Sato, Y. et al. Silodosin and its potential for treating premature ejaculation: a preliminary report. Int. J. Urol. 19, 268–272 (2012).

    Article  CAS  PubMed  Google Scholar 

  222. Bhat, G. S. & Shastry, A. Effectiveness of ‘on demand’ silodosin in the treatment of premature ejaculation in patients dissatisfied with dapoxetine: a randomized control study. Cent. Eur. J. Urol. 69, 280–284 (2016).

    CAS  Google Scholar 

  223. Hwang, E. C. et al. Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. Cochrane Database Syst. Rev. 10, CD007360 (2018).

    PubMed  Google Scholar 

  224. Sato, Y. et al. Silodosin versus naftopidil in the treatment of premature ejaculation: a prospective multicenter trial. Int. J. Urol. 24, 626–631 (2017).

    Article  CAS  PubMed  Google Scholar 

  225. Bhat, G. S. & Shastry, A. A prospective double-blind, randomized, placebo-controlled study to evaluate the efficacy of silodosin 8 mg as an on-demand, reversible, nonhormonal oral contraceptive for males: a pilot study. World J. Urol. 38, 747–751 (2020).

    Article  CAS  PubMed  Google Scholar 

  226. Liu, N., Yang, H., Han, L. & Ma, M. Oxytocin in women’s health and disease. Front. Endocrinol. https://doi.org/10.3389/fendo.2022.786271 (2022).

    Article  Google Scholar 

  227. de Jong, T. R., Veening, J. G., Olivier, B. & Waldinger, M. D. Oxytocin involvement in SSRI-induced delayed ejaculation: a review of animal studies. J. Sex. Med. 4, 14–28 (2007).

    Article  PubMed  Google Scholar 

  228. Stoneham, M. D., Everitt, B. J., Hansen, S., Lightman, S. L. & Todd, K. Oxytocin and sexual behaviour in the male rat and rabbit. J. Endocrinol. 107, 97–106 (1985).

    Article  CAS  PubMed  Google Scholar 

  229. Arletti, R., Benelli, A. & Bertolini, A. Sexual behavior of aging male rats is stimulated by oxytocin. Eur. J. Pharmacol. 179, 377–381 (1990).

    Article  CAS  PubMed  Google Scholar 

  230. Clement, P. et al. Inhibition of ejaculation by the non-peptide oxytocin receptor antagonist GSK557296: a multi-level site of action. Br. J. Pharmacol. 169, 1477–1485 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Shinghal, R. et al. Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study. J. Sex. Med. 10, 2506–2517 (2013).

    Article  CAS  PubMed  Google Scholar 

  232. Wayman, C. et al. Cligosiban, a novel brain-penetrant, selective oxytocin receptor antagonist, inhibits ejaculatory physiology in rodents. J. Sex. Med. 15, 1698–1706 (2018).

    Article  PubMed  Google Scholar 

  233. McMahon, C. et al. The oxytocin antagonist cligosiban prolongs intravaginal ejaculatory latency and improves patient-reported outcomes in men with lifelong premature ejaculation: results of a randomized, double-blind, placebo-controlled proof-of-concept trial (PEPIX). J. Sex. Med. 16, 1178–1187 (2019).

    Article  PubMed  Google Scholar 

  234. Althof, S., Osterloh, I. H., Muirhead, G. J., George, K. & Girard, N. The oxytocin antagonist cligosiban fails to prolong intravaginal ejaculatory latency in men with lifelong premature ejaculation: results of a randomized, double-blind, placebo-controlled phase IIb trial (PEDRIX). J. Sex. Med. 16, 1188–1198 (2019).

    Article  PubMed  Google Scholar 

  235. Gul, M. & Serefoglu, E. C. Oxytocin antagonists: the next frontier in PE treatment. Nat. Rev. Urol. 16, 696–697 (2019).

    Article  PubMed  Google Scholar 

  236. David Prologo, J. et al. Percutaneous CT-guided cryoablation of the dorsal penile nerve for treatment of symptomatic premature ejaculation. J. Vasc. Interv. Radiol. 24, 214–219 (2013).

    Article  CAS  PubMed  Google Scholar 

  237. Zhang, G. X., Yu, L. P., Bai, W. J. & Wang, X. F. Selective resection of dorsal nerves of penis for premature ejaculation. Int. J. Androl. 35, 873–879 (2012).

    Article  PubMed  Google Scholar 

  238. Zhang, C. Y. et al. [Regional anatomy of the dorsal penile nerve and its clinical significance]. Zhonghua Nan Ke Xue 15, 130–133 (2009).

    PubMed  Google Scholar 

  239. Shi, W. G. et al. [Selective resection of the branches of the two dorsal penile nerves for primary premature ejaculation]. Zhonghua Nan Ke Xue 14, 436–438 (2008).

    PubMed  Google Scholar 

  240. Liu, Q. et al. Anatomic basis and clinical effect of selective dorsal neurectomy for patients with lifelong premature ejaculation: a randomized controlled trial. J. Sex. Med. 16, 522–530 (2019).

    Article  PubMed  Google Scholar 

  241. Zhang, H. F., Zhang, C. Y., Li, X. H., Fu, Z. Z. & Chen, Z. Y. Dorsal penile nerves and primary premature ejaculation. Chin. Med. J. 122, 3017–3019 (2009).

    PubMed  Google Scholar 

  242. Moon, D. G. et al. Augmentation of glans penis using injectable hyaluronic acid gel. Int. J. Impot. Res. 15, 456–460 (2003).

    Article  CAS  PubMed  Google Scholar 

  243. Kim, J. J., Kwak, T. I., Jeon, B. G., Cheon, J. & Moon, D. G. Effects of glans penis augmentation using hyaluronic acid gel for premature ejaculation. Int. J. Impot. Res. 16, 547–551 (2004).

    Article  CAS  PubMed  Google Scholar 

  244. Kwak, T. I., Jin, M. H., Kim, J. J. & Moon, D. G. Long-term effects of glans penis augmentation using injectable hyaluronic acid gel for premature ejaculation. Int. J. Impot. Res. 20, 425–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  245. Abdallah, H. et al. Treatment of premature ejaculation by glans penis augmentation using hyaluronic acid gel: a pilot study. Andrologia 44 (Suppl. 1), 650–653 (2012).

    Article  PubMed  Google Scholar 

  246. Alahwany, A., Ragab, M. W., Zaghloul, A., Abdallah, H. & Mostafa, T. Hyaluronic acid injection in glans penis for treatment of premature ejaculation: a randomized controlled cross-over study. Int. J. Impot. Res. https://doi.org/10.1038/s41443-018-0104-9 (2019).

    Article  PubMed  Google Scholar 

  247. Gul, M. Comment on “Hyaluronic acid injection in glans penis for treatment of premature ejaculation: a randomized controlled cross-over study”. Int. J. Impot. Res. https://doi.org/10.1038/s41443-019-0200-5 (2019).

    Article  PubMed  Google Scholar 

  248. Ahn, S. T., Il Kwak, T., Park, K. S., Kim, J. J. & Moon, D. G. Complications of glans penis augmentation. Int. J. Impot. Res. 31, 245–255 (2019).

    Article  PubMed  Google Scholar 

  249. Zhang, C. et al. Efficacy and safety assessment of glandular augmentation with hyaluronic acid for premature ejaculation. Andrologia https://doi.org/10.1111/and.14435 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  250. Shebl, S. E., Ali, S. & Shokr, M. Hyaluronic acid injection in the glans penis for the treatment of refractory premature ejaculation: a prospective, controlled study. Andrologia 53, e14084 (2021).

    Article  CAS  PubMed  Google Scholar 

  251. Moon du, G., Kwak, T. I. & Kim, J. J. Glans penis augmentation using hyaluronic acid gel as an injectable filler. World J. Mens. Health 33, 50–61 (2015).

    Article  PubMed  Google Scholar 

  252. Huang, W., Foster, J. A. & Rogachefsky, A. S. Pharmacology of botulinum toxin. J. Am. Acad. Dermatol. 43, 249–259 (2000).

    Article  CAS  PubMed  Google Scholar 

  253. Jankovic, J. Botulinum toxin in clinical practice. J. Neurol. Neurosurg. Psychiatry 75, 951–957 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Jost, W. H. & Naumann, M. Botulinum toxin in neuro-urological disorders. Mov. Disord. 19, S142–S145 (2004).

    Article  PubMed  Google Scholar 

  255. Serefoglu, E. C. & Silay, M. S. Botulinum toxin-A injection may be beneficial in the treatment of life-long premature ejaculation. Med. Hypotheses 74, 83–84 (2010).

    Article  CAS  PubMed  Google Scholar 

  256. Gerstenberg, T. C., Levin, R. J. & Wagner, G. Erection and ejaculation in man. Assessment of the electromyographic activity of the bulbocavernosus and ischiocavernosus muscles. Br. J. Urol. 65, 395–402 (1990).

    Article  CAS  PubMed  Google Scholar 

  257. Serefoglu, E. C. et al. Effect of botulinum-A toxin injection into bulbospongiosus muscle on ejaculation latency in male rats. J. Sex. Med. 11, 1657–1663 (2014).

    Article  CAS  PubMed  Google Scholar 

  258. Ongun, S. et al. Can botulinum-A toxin be used to delay ejaculation: results of an ejaculation model in male rats. J. Sex. Med. 16, 1338–1343 (2019).

    Article  PubMed  Google Scholar 

  259. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01917006 (2018).

  260. Li, Z. T. et al. [Injection of botulinum-A toxin into bulbospongiosus muscle for primary premature ejaculation: a preliminary clinical study]. Zhonghua Nan Ke Xue 24, 713–718 (2018).

    PubMed  Google Scholar 

  261. Aoki, K. R. J. Pharmacology and immunology of botulinum toxin serotypes. J. Neurol. 248 (Suppl. 1), 3–10 (2001).

    Article  CAS  PubMed  Google Scholar 

  262. Chermansky, C. J. & Chancellor, M. B. Use of botulinum toxin in urologic diseases. Urology 91, 21–32 (2016).

    Article  PubMed  Google Scholar 

  263. Pischedda, A., Fusco, F., Curreli, A., Grimaldi, G. & Farina, F. P. Pelvic floor and sexual male dysfunction. Arch. Ital. Urol. Nefrol. Androl. 85, 1–7 (2013).

    Article  Google Scholar 

  264. Screponi, E. et al. Prevalence of chronic prostatitis in men with premature ejaculation. Urology 58, 198–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  265. Pastore, A. L. et al. Pelvic floor muscle rehabilitation for patients with lifelong premature ejaculation: a novel therapeutic approach. Ther. Adv. Urol. 6, 83–88 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  266. Pastore, A. et al. A prospective randomized study to compare pelvic floor rehabilitation and dapoxetine for treatment of lifelong premature ejaculation. Int. J. Androl. 35, 528–533 (2012).

    Article  CAS  PubMed  Google Scholar 

  267. Pastore, A. L. et al. Pelvic muscle floor rehabilitation as a therapeutic option in lifelong premature ejaculation: long-term outcomes. Asian J. Androl. 20, 572–575 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  268. Gruenwald, I. et al. Transcutaneous neuromuscular electrical stimulation may be beneficial in the treatment of premature ejaculation. Med. Hypotheses 109, 181–183 (2017).

    Article  PubMed  Google Scholar 

  269. Shechter, A. et al. Transcutaneous functional electrical stimulation — a novel therapy for premature ejaculation: results of a proof of concept study. Int. J. Impot. Res. https://doi.org/10.1038/s41443-019-0207-y (2019).

    Article  PubMed  Google Scholar 

  270. Peyronnet, B., Amarenco, G., Kerdraon, J., Cornu, J. N. & Gamé, X. Transcutaneous posterior tibial nerve stimulation: ready for prime time. Neurourol. Urodyn. 38, 1024–1025 (2019).

    Article  PubMed  Google Scholar 

  271. Polat Dunya, C., Tulek, Z., Kürtüncü, M., Panicker, J. N. & Eraksoy, M. Effectiveness of the transcutaneous tibial nerve stimulation and pelvic floor muscle training with biofeedback in women with multiple sclerosis for the management of overactive bladder. Mult. Scler. 27, 621–629 (2021).

    Article  PubMed  Google Scholar 

  272. Giuliano, F. Neurophysiology of erection and ejaculation. J. Sex. Med. 8 (Suppl. 4), 310–315 (2011).

    Article  PubMed  Google Scholar 

  273. Puppo, V. & Puppo, G. Comprehensive review of the anatomy and physiology of male ejaculation: premature ejaculation is not a disease. Clin. Anat. 29, 111–119 (2016).

    Article  PubMed  Google Scholar 

  274. Uribe, O. L., Sandoval-Salinas, C., Corredor, H. A., Martínez, J. M. & Saffon, J. P. Transcutaneous electric nerve stimulation to treat patients with premature ejaculation: phase II clinical trial. Int. J. Impot. Res. https://doi.org/10.1038/s41443-019-0196-x (2019).

    Article  PubMed  Google Scholar 

  275. Aydos, M. M., Nas, I. & Önen, E. The impact of transcutaneous posterior tibial nerve stimulation in patients with premature ejaculation. Eur. Res. J. https://doi.org/10.18621/eurj.565190 (2020).

    Article  Google Scholar 

  276. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04207723 (2020).

  277. Zavatti, M. et al. Experimental study on Satureja montana as a treatment for premature ejaculation. J. Ethnopharmacol. 133, 629–633 (2011).

    Article  CAS  PubMed  Google Scholar 

  278. Sansalone, S. et al. A combination of tryptophan, Satureja montana, Tribulus terrestris, Phyllanthus emblica extracts is able to improve sexual quality of life in patient with premature ejaculation. Arch. Ital. Urol. Androl. 88, 171–176 (2016).

    Article  PubMed  Google Scholar 

  279. Sansalone, S. et al. Alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide improve erectile function, sexual quality of life, and ejaculation function in patients with moderate mild-moderate erectile dysfunction: a prospective, randomized, placebo-controlled, single-blinded study. Biomed. Res. Int. 2014, 121396 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  280. Cai, T. et al. Rhodiola rosea, folic acid, zinc and biotin (EndEP®) is able to improve ejaculatory control in patients affected by lifelong premature ejaculation: results from a phase I–II study. Exp. Ther. Med. 12, 2083–2087 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Cai, T. et al. The role of diallyl thiosulfinate associated with nuciferine and diosgenin in the treatment of premature ejaculation: a pilot study. Arch. Ital. Urol. Androl. 90, 59–64 (2018).

    Article  CAS  PubMed  Google Scholar 

  282. Saadat, S. H., Ahmadi, K. & Panahi, Y. The effect of on-demand caffeine consumption on treating patients with premature ejaculation: a double-blind randomized clinical trial. Curr. Pharm. Biotechnol. 16, 281–287 (2015).

    Article  CAS  PubMed  Google Scholar 

  283. Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Chen, Z. et al. Significance of piezo-type mechanosensitive ion channel component 2 in premature ejaculation: an animal study. Andrology 8, 1347–1359 (2020).

    Article  CAS  PubMed  Google Scholar 

  285. Huang, Y. et al. Expression of brain-derived neurotrophic factor in rapid ejaculator rats: a further study. Andrologia https://doi.org/10.1111/and.14134 (2021).

    Article  PubMed  Google Scholar 

  286. Miranda, M., Morici, J. F., Zanoni, M. B. & Bekinschtein, P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front. Cell. Neurosci. https://doi.org/10.3389/fncel.2019.00363 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  287. Waldinger, M. D. & Schweitzer, D. H. Differences between ICD-11 MMS and DSM-5 definition of premature ejaculation: a continuation of historical inadequacies and a source of serious misinterpretation by some European Regulatory Agencies (PART 2). Int. J. Impot. Res. 31, 310–318 (2019).

    Article  PubMed  Google Scholar 

  288. Waldinger, M. D. & Schweitzer, D. H. Method and design of drug treatment research of subjective premature ejaculation in men differs from that of lifelong premature ejaculation in males: proposal for a new objective measure (part 1). Int. J. Impot. Res. 31, 328–333 (2019).

    Article  PubMed  Google Scholar 

  289. Janssen, P. K. C. & Waldinger, M. D. Use of a confirmed mathematical method for back-analysis of IELT distributions: ejaculation time differences between two continents and between continents and men with lifelong premature ejaculation (Part 1). Int. J. Impot. Res. 31, 334–340 (2019).

    Article  PubMed  Google Scholar 

  290. Janssen, P. K. C. & Waldinger, M. D. Men with subjective premature ejaculation have a similar lognormal IELT distribution as men in the general male population and differ mathematically from males with lifelong premature ejaculation after an IELT of 1.5 minutes (Part 2). Int. J. Impot. Res. 31, 341–347 (2019).

    Article  PubMed  Google Scholar 

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M.G. and K.B. researched data for the article. All authors contributed substantially to discussion of the content. M.G. and K.B. wrote the article. E.C.S. reviewed and edited the manuscript before submission.

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Gul, M., Bocu, K. & Serefoglu, E.C. Current and emerging treatment options for premature ejaculation. Nat Rev Urol 19, 659–680 (2022). https://doi.org/10.1038/s41585-022-00639-5

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