Advertisement

Evolution of the Understanding of Premature Ejaculation: Historical Perspectives

  • Marcel D. Waldinger
    Correspondence
    Department of Psychiatry and Neurosexology, Haga Hospital Leyenburg, Leyweg 275, 2545 CH The Hague, The Netherlands. Tel. +31 70 3592086; Fax: +31 70 3594902.
    Affiliations
    Department of Psychiatry and Neurosexology, Haga Hospital Leyenburg, The Hague, The Netherlands

    Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, The Netherlands
    Search for articles by this author

      Abstract

      The perception of lifelong premature ejaculation (PE) has evolved from that of a relatively obscure complaint to one of a relatively common syndrome with a neurobiological component. During the last century, four historical periods, each about 30 yr in duration, can be distinguished. In these periods PE was regarded according to the major prevailing viewpoint of mental disorders, that is, from phenomenological, psychoanalytic, behavioral, and neurobiological points of view. Although the influences of these different periods on the medical approach to PE are still present today, recent scientific evidence suggests that lifelong PE is related to an imbalance in central serotonin neurotransmission. A basic premise for further research remains an evidence-based definition of PE. Such an evidence-based definition is essential to ensure accurate and reproducible clinical outcomes.

      Keywords

      1. Introduction

      Scientific and medical perspectives on premature ejaculation (PE) have evolved throughout the last century. Although PE was considered as nothing more than a peculiar anomaly until about 1917, it was believed to be mainly a psychological disorder for the first half of the 20th century [
      • Waldinger M.D.
      The neurobiological approach to premature ejaculation.
      ,
      • Waldinger M.D.
      Lifelong premature ejaculation: from authority-based to evidence-based medicine.
      ]. During the 1960s, the perspective shifted to the view that PE was not a symptom of a neurosis but a manifestation of self-learned behavior. Today, in contrast, individuals who have experienced PE from the time of their first sexual encounter as well as many of those who develop PE after a period of normal ejaculatory function are considered to have lifelong and acquired PE, respectively [
      • Waldinger M.D.
      Emerging drugs for premature ejaculation.
      ]. However, although lifelong PE is regarded to be highly neurobiologically determined, and acquired PE may have both a medical and a psychological basis [
      • Olivier B.
      • van Oorschot R.
      • Waldinger M.D.
      Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual behaviour.
      ], the etiologies of both types of PE are still not completely understood.
      Our current understanding of the neurobiological basis of PE was reached primarily through animal studies and, particularly in the 1990s, through an increasing number of drug treatment studies with selective serotonin reuptake inhibitors (SSRIs) and clomipramine [
      • Ahlenius S.
      • Larsson K.
      Failure to antagonize the 8-hydroxy-2-di-n-propylaminotetralin-induced facilitation of male rat sexual behavior by the administration of 5-HT receptor antagonists.
      ,
      • Bitran D.
      • Hull E.M.
      Pharmacological analysis of male rat sexual behavior.
      ,
      • 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.
      ]. These studies have demonstrated a key role of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor subtypes in regulating ejaculation [
      • Olivier B.
      • van Oorschot R.
      • Waldinger M.D.
      Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual behaviour.
      ,
      • 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.
      ].
      For many years there have been two separate and rather contrasting approaches to PE: the medical approach favoring drug treatment and the psychological approach focusing on behavioral therapy of PE. A current challenge in PE treatment is to combine psychological and neurobiological insights into an evidence-based definition of PE. This review will focus on the historical viewpoints and the current neurobiological approach of PE.

      2. Historical perspectives of premature ejaculation

      2.1 The first period: phenomenological

      After the first report of PE in the medical literature in 1887 [
      • Gross S.
      Practical treatise on impotence and sterility.
      ], a period of 30 yr ensued in which PE was regarded as only a rather “disturbing” symptom and for which no etiology was suggested.

      2.2 The second period: psychoanalytic

      The psychoanalytic period began in 1917 when Karl Abraham, a psychoanalyst, ascribed PE to a neurosis, that is, as the symptom of unsolved unconscious conflicts, and advocated treatment by classical psychoanalysis [
      • Abraham K.
      Ueber ejaculatio praecox, Zeitschr.
      ]. His purely psychological explanation was later challenged by Bernard Schapiro, a German psychiatrist, who in 1943 postulated that PE was not a neurotic but a psychosomatic disorder [
      • Schapiro B.
      Premature ejaculation: a review of 1130 cases.
      ]. He argued that both biological and psychological factors contributed to rapid ejaculatory performances. Years ahead of his time, Schapiro advocated drug treatment in the form of anesthetic ointments to delay ejaculation. In addition, he is credited with identifying the two types of PE recognized today as primary (lifelong) and secondary (acquired) PE [
      • Schapiro B.
      Premature ejaculation: a review of 1130 cases.
      ]. Because he was the first clinician to use a medical approach to PE, Bernard Schapiro is regarded as a pioneer in researching this condition.
      The accurate differential diagnosis and biologic components of Schapiro's arguments were ignored in his time. Psychoanalytic treatment, mainly conducted by psychiatrists, prevailed throughout the 1940s and 1950s. Records of the course and results of these psychoanalytic treatments could have provided insights into how this medical condition affects unconscious processes and its unconscious impact on neurotic adaptations to daily life. For example, considered from a classical Freudian perspective, it may be relevant whether individuals cope differently with lifelong PE dependent on more anal, oral, or oedipal period neurotic fixations [
      • Waldinger M.D.
      The need for a revival of psychoanalytic investigations into premature ejaculation.
      ]. Unfortunately, very little of this information is documented in the literature.

      2.3 The third period: behavioristic

      In the mid-1960s, concurrent with a rejection of psychoanalysis and an increasing popularity of behaviorism in academic psychology, the approach and treatment of sexual disorders began to evolve. Although originally borne out of psychiatry and handled mainly by psychiatrists, sexology now became the field of psychologists and sexologists who, particularly in those years of antipsychiatry, demonstrated an overt aversion to psychoanalysis, and the medical and drug treatment approach of mental and sexual disorders. The rejection of the medical and psychoanalytic roots of sexual dysfunctions contributed to the separation and isolation of sexology from psychiatry and ultimately also from academic medicine, a separation that still exists today. It is with this background that one has to consider the third period of PE, the behavioristic period. This perspective started in 1970 when Masters and Johnson [
      • Masters W.
      • Johnson V.
      Premature ejaculation.
      ] published their book in which they argued that PE was the result of a self-learned behavior, meaning that PE became acquired by hurried intercourse during initial sexual experiences. Masters and Johnson stated that PE could be cured through behavioral therapy in the form of the squeeze technique, a masturbation technique that resembled the older stop-start method of Semans [
      • Masters W.
      • Johnson V.
      Premature ejaculation.
      ,
      • Semans J.H.
      Premature ejaculation: a new approach.
      ]. Their ideas on PE prevailed until very recently, despite the lack of evidence-based studies to support their theories of etiology and treatment effectiveness. For a period of 20–30 yr, with little exception [
      • Zilbergeld B.
      • Evans M.
      The inadequacy of Masters and Johnson.
      ], authors did not criticize the lack of evidence for the theories of Masters and Johnson. Moreover, various sexologists, competing to improve upon their theory, proposed shortening the duration of the behavioral treatment as proposed by Masters and Johnson. In this way it was proposed to have only limited sessions and/or limited telephone contacts with the patient because it was assumed that solely practicing the masturbation exercises would automatically ameliorate the problem [
      • Clement U.
      • Schmidt G.
      The outcome of couple therapy for sexual dysfunctions using three different formats.
      ,
      • Trudel G.
      • Proulx S.
      Treatment of premature ejaculation by bibliotherapy: an experimental study.
      ]. A failure of behavioral therapy to delay ejaculation was often ascribed to the patient not practicing the exercises in the appropriate manner. This early approach of sexologists to diminish the frequency of face-to-face contacts with men with PE highly contrasts with the current view. Today, many sexologists insist on “talking” with the couple and emphasize the inadequacies of using medication exclusively to delay ejaculation.
      During the period of behavioral treatment, case reports and placebo-controlled studies described the efficacy of the tricyclic antidepressant clomipramine in delaying ejaculation [
      • Eaton H.
      Clomipramine in the treatment of premature ejaculation.
      ,
      • Porto R.
      Essai en double aveugle de la clomipramine dans l’ejaculation prematuree.
      ,
      • Assalian P.
      Clomipramine in the treatment of premature ejaculation.
      ]. These studies, although often not conducted according to current standards of evidence-based medicine, paved the way for the increasing popularity of oral drug treatment of PE.

      2.4 The fourth period: neurobiological

      In the mid-1990s the introduction of the selective serotonin reuptake inhibitors (SSRIs) brought about a revolutionary change in the understanding and treatment of PE. Their efficacy in delaying ejaculation together with the increasing interest of neuroscientists, like Sven Ahlenius [
      • Ahlenius S.
      • Larsson K.
      Failure to antagonize the 8-hydroxy-2-di-n-propylaminotetralin-induced facilitation of male rat sexual behavior by the administration of 5-HT receptor antagonists.
      ,
      • Ahlenius S.
      • Larsson K.
      Evidence for an involvement of 5-HT1B receptors in the inhibition of male rat ejaculatory behavior produced by 5-HTP.
      ], in investigating sexual behavior in laboratory rats led to the end of the supremacy of the behavioristic approach of PE and marked the beginning of the neurobiological view. Animal studies and the use of stopwatch assessment of the intravaginal ejaculatory latency time (IELT) [
      • Waldinger M.D.
      • Hengeveld M.W.
      • Zwinderman A.H.
      Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study.
      ] both during the baseline period and during drug treatment led to a more evidence-based approach of drug treatment trials [
      • Pattij T.
      • de Jong T.
      • Uitterdijk A.
      • et al.
      Individual differences in male rat ejaculatory behavior: searching for models to study ejaculation disorders.
      ,
      • Waldinger M.D.
      Towards evidence-based drug treatment research on premature ejaculation: a critical evaluation of methodology.
      ].

      2.4.1 The role of serotonin in ejaculatory motor control

      Experimental studies demonstrated that serotonin and serotonin receptors modulate motor control of ejaculation in animals [
      • Ahlenius S.
      • Larsson K.
      Failure to antagonize the 8-hydroxy-2-di-n-propylaminotetralin-induced facilitation of male rat sexual behavior by the administration of 5-HT receptor antagonists.
      ,
      • 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.
      ]. In addition, animal studies have shown that a diminished serotonin neurotransmission and activation of 5-HT1A receptors lead to faster ejaculation, whereas activation of 5-HT2C and 5-HT1B receptors delays ejaculation [
      • Ahlenius S.
      • Larsson K.
      Failure to antagonize the 8-hydroxy-2-di-n-propylaminotetralin-induced facilitation of male rat sexual behavior by the administration of 5-HT receptor antagonists.
      ,
      • 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.
      ,
      • Giuliano F.
      • Clement P.
      Serotonin and premature ejaculation: from physiology to patient management.
      ]. Although the efficacy of SSRIs in the treatment of PE argues for a similar role in humans, there is no evidence to date that these specific 5-HT receptors are involved in human ejaculation [
      • Waldinger M.D.
      The neurobiological approach to premature ejaculation.
      ].

      2.4.2 Definition of PE

      There is accumulating evidence for a neurobiological basis of lifelong PE, despite the contrasting and conflicting medical and psychological approaches to PE that prevailed until the mid-1990s. However, an official evidence-based definition of PE is still lacking. The definition of PE as formulated in the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR) issued by the American Psychiatric Association (APA) is “persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it” [

      American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th edition, text revision) (DSM-IV-TR). Washington, American Psychiatric Association; 2000.

      ]. The DSM requires that “the disturbance causes marked distress or interpersonal difficulty” [

      American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th edition, text revision) (DSM-IV-TR). Washington, American Psychiatric Association; 2000.

      ]. This definition is vague because it fails to operationalize “marked distress” and “marked interpersonal difficulty.” The definition issued by the American Urological Association (AUA) Guideline on the Management of Premature Ejaculation, “ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners,” is similarly vague as it is nearly an exact copy of the DSM definition [
      • Montague D.K.
      • Jarow J.
      • Broderick G.A.
      • et al.
      AUA guideline on the pharmacologic management of premature ejaculation.
      ,
      • Waldinger M.D.
      Overview of premature and retarded ejaculation.
      ]. Both the definitions offered by the APA and the AUA are not based on controlled studies, but the result of expert (authority) consensus [
      • 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 I—validity of DSM-IV-TR.
      ,
      • 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.
      ]. Recently, however, and based on controlled studies, Waldinger and Schweitzer [
      • 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 I—validity of DSM-IV-TR.
      ,
      • 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.
      ] proposed a new “syndromal” instead of “subjective complaint” approach to define PE in the pending DSM-V and ICD-11 editions.

      2.4.3 Intravaginal ejaculation latency time

      An important issue in neurobiological research is the reproducibility of quantified data by the use of operationally defined measures and reliable instruments. To address this need in PE research, Waldinger et al [
      • Waldinger M.D.
      • Hengeveld M.W.
      • Zwinderman A.H.
      Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study.
      ] emphasized the clinical and scientific importance of the ejaculation time and introduced the measurement of IELT, which is defined as the time between vaginal intromission and intravaginal ejaculation. Waldinger et al [
      • 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.
      ] further postulated that the IELT is neurobiologically determined and variably distributed both in the general male population and in men with lifelong PE. Indeed, such a continuum of the IELT was found in a clinical cohort of 110 men with complaints of lifelong PE. In this population, the IELT was ≤30 s in 80%, between 40 and 60 s in approximately 10%, and between 1 and 2 min in the remaining 10% [
      • Waldinger M.D.
      • Hengeveld M.W.
      • Zwinderman A.H.
      • Olivier B.
      An empirical operationalization study of DSM-IV diagnostic criteria for premature ejaculation.
      ].

      2.4.4 Defining abnormal IELTs

      To determine the distribution of IELTs in the general male population, Waldinger et al [
      • Waldinger M.D.
      • Quinn P.
      • Dilleen M.
      • Mundayat R.
      • Schweitzer D.H.
      • Boolell M.
      A multi-national population survey of intravaginal ejaculation latency time.
      ] conducted a stopwatch study in a random cohort of 491 men among five nations (the Netherlands, United Kingdom, Spain, Turkey, and the United States). To ensure a random cohort of men enrolled in the study, they did not apply inclusion and exclusion criteria. Because the distribution of IELTs did not fall on a bell-shaped curve, analysis using percentiles was used. Currently accepted statistical methods use cut-offs of 0.5–2.5 percentiles to define abnormal values in skewed populations such as this one [
      ]. Men who were below the 0.5 percentile reported IELTs <1 min, and those in the range of 0.5–2.5 percentiles reported IELTs between 1.0 and 1.5 min [
      • Waldinger M.D.
      • Zwinderman A.H.
      • Olivier B.
      • Schweitzer D.H.
      Proposal for a definition of lifelong premature ejaculation based on epidemiological stopwatch data.
      ]. On the basis of these IELTs, Waldinger et al [
      • Waldinger M.D.
      • Zwinderman A.H.
      • Olivier B.
      • Schweitzer D.H.
      Proposal for a definition of lifelong premature ejaculation based on epidemiological stopwatch data.
      ] proposed that “definite” PE be defined by an IELT <1 min and “probable” PE by an IELT between 1.0 and 1.5 min, indicating that the risk to develop complaints of PE becomes higher when the IELT gets shorter. Within those categories, the severity of PE was further classified on a four-point scale of “none,” “mild,” “moderate,” or “severe” as determined by psychological and sexual distress. The 1-min cut-off IELT is consistent with data from a clinical study by Waldinger et al [
      • Waldinger M.D.
      • Hengeveld M.W.
      • Zwinderman A.H.
      • Olivier B.
      An empirical operationalization study of DSM-IV diagnostic criteria for premature ejaculation.
      ], in which 90% of men actively complaining of PE ejaculated within 1 min.

      2.4.5 Treatment with SSRIs

      The first double-blind placebo-controlled study on the efficacy of paroxetine to delay ejaculation in men with PE was published in 1994 [
      • Waldinger M.D.
      • Hengeveld M.W.
      • Zwinderman A.H.
      Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study.
      ]. Subsequent studies have shown that daily treatment with paroxetine [
      • Waldinger M.D.
      • Hengeveld M.W.
      • Zwinderman A.H.
      Ejaculation-retarding properties of paroxetine in patients with primary premature ejaculation: a double-blind, randomized, dose-response study.
      ,
      • 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.
      ] and sertraline [
      • 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.
      ,
      • Mendels J.
      • Camera A.
      • Sikes C.
      Sertraline treatment for premature ejaculation.
      ,
      • Balbay M.D.
      • Yildiz M.
      • Salvarci A.
      • Ozsar O.
      • Ozbek E.
      Treatment of premature ejaculation with sertralin.
      ] can significantly prolong IELT in patients with PE. Also, fluoxetine [
      • 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.
      ,
      • Kara H.
      • Aydin S.
      • Yucel M.
      • Aqarqun M.Y.
      • Odabas O.
      • Yilmaz Y.
      The efficacy of fluoxetine in the treatment of premature ejaculation: a double-blind placebo controlled study.
      ,
      • Lee H.S.
      • Song D.H.
      • Kim C.H.
      • Choi H.K.
      An open clinical trial of fluoxetine in the treatment of premature ejaculation.
      ] has been proven efficacious with continuous dosing as has the tricyclic antidepressant clomipramine [
      • 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.
      ]. However, the on-demand use of these SSRIs [
      • McMahon C.G.
      • Touma K.
      Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies.
      ,
      • Murat Basar M.A.
      • Atan A.
      • Yildiz M.
      • Baykam M.
      • Aydoganli L.
      Comparison of sertraline to fluoxetine with regard to their efficacy and side effects in the treatment of premature ejaculation.
      ,
      • 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.
      ,
      • 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.
      ,
      • Rivera P.
      • Gonzalez R.
      • Gonzalez F.
      • Storme O.
      Use of paroxetine on-demand in premature ejaculation [in Spanish].
      ] has resulted in contrasting results that presumably are due to methodological insufficiencies [
      • 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.
      ]. To date, none of these agents has received US Food and Drug Administration approval for treatment of PE.
      Although daily treatment with SSRIs clinically relevantly delays ejaculation, the requirement for continuous use of SSRIs, particularly for men with lifelong PE, may hamper patient compliance in the long term. Moreover, evidence suggests that acute effects of SSRI treatments may be limited by inherent neurotransmission feedback mechanisms [
      • 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.
      ]. Therefore, continuous research is being encouraged to develop and investigate new drugs to treat PE.

      3. Conclusion

      Although PE has been an identified male sexual complaint for many centuries, it was described in the medical literature for the first time in 1887. Since then, four distinct areas of PE have evolved on the basis of the prevailing theories of mental and/or sexual disorders of each period. The current view of PE is in accordance with the present day understanding of the physiological basis of mental disorders. This “Neurobiological Period” started in the mid 1990s after the introduction of the SSRIs and has led to an expanding body of knowledge about the factors underlying PE.
      The historical perspectives taken from earlier periods have contributed to our current understanding of PE. However, few well-controlled studies were performed during the psychoanalytic and behavioral periods. Documentation of how lifelong PE affects the unconscious minds of men affected by this dysfunction and placebo–controlled, comparative studies using IELT measurements to assess the efficacy of behavioral treatments would be valuable in determining the value of these modalities in treating patients with PE. In the current “area of neurobiology,” neuroscientific and psychopharmacological research has contributed highly to the availability of effective drugs to treat PE. Still, continuous research is encouraged and needed to develop and investigate new drugs for the treatment of PE. However, as we move forward with the research and treatment of PE, a basic condition for any further research remains an evidence-based definition of PE. Such an evidence-based definition, as has recently been proposed in terms of a syndromal PE approach, is essential to ensure accurate and reproducible clinical outcomes.

      Conflicts of interest

      The author has nothing to disclose.

      References

        • Waldinger M.D.
        The neurobiological approach to premature ejaculation.
        J Urol. 2002; 168: 2359-2367
        • Waldinger M.D.
        Lifelong premature ejaculation: from authority-based to evidence-based medicine.
        BJU Int. 2004; 93: 201-207
        • Waldinger M.D.
        Emerging drugs for premature ejaculation.
        Expert Opin Emerg Drugs. 2006; 11: 99-109
        • Olivier B.
        • van Oorschot R.
        • Waldinger M.D.
        Serotonin, serotonergic receptors, selective serotonin reuptake inhibitors and sexual behaviour.
        Int Clin Psychopharmacol. 1998; 13: S9-S14
        • Ahlenius S.
        • Larsson K.
        Failure to antagonize the 8-hydroxy-2-di-n-propylaminotetralin-induced facilitation of male rat sexual behavior by the administration of 5-HT receptor antagonists.
        Eur J Pharmacol. 1984; 99: 279-286
        • Bitran D.
        • Hull E.M.
        Pharmacological analysis of male rat sexual behavior.
        Neurosci Biobehav Rev. 1987; 11: 365-389
        • 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. 2004; 16: 369-381
        • 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. 1998; 92: 111-118
        • Gross S.
        Practical treatise on impotence and sterility.
        YJ Pentland, Edinburgh1887
        • Abraham K.
        Ueber ejaculatio praecox, Zeitschr.
        Aerztl Psychoanal. 1917; 4: 171-186
        • Schapiro B.
        Premature ejaculation: a review of 1130 cases.
        J Urol. 1943; 50: 374-379
        • Waldinger M.D.
        The need for a revival of psychoanalytic investigations into premature ejaculation.
        J Mens Health Gender. 2006; 3: 390-396
        • Masters W.
        • Johnson V.
        Premature ejaculation.
        in: Masters W. Johnson V. Human sexual inadequacy. Little, Brown, Boston1970: 92-115
        • Semans J.H.
        Premature ejaculation: a new approach.
        South Med J. 1956; 49: 353-357
        • Zilbergeld B.
        • Evans M.
        The inadequacy of Masters and Johnson.
        Psychology Today. 1980; 14: 29-34
        • Clement U.
        • Schmidt G.
        The outcome of couple therapy for sexual dysfunctions using three different formats.
        J Sex Marital Ther. 1983; 9: 67-78
        • Trudel G.
        • Proulx S.
        Treatment of premature ejaculation by bibliotherapy: an experimental study.
        Sex Marital Ther. 1987; 2: 163-167
        • Eaton H.
        Clomipramine in the treatment of premature ejaculation.
        J Int Med Res. 1973; 1: 432-434
        • Porto R.
        Essai en double aveugle de la clomipramine dans l’ejaculation prematuree.
        Med Hygiene. 1981; 39: 1249-1253
        • Assalian P.
        Clomipramine in the treatment of premature ejaculation.
        J Sex Res. 1988; 24: 213-215
        • Ahlenius S.
        • Larsson K.
        Evidence for an involvement of 5-HT1B receptors in the inhibition of male rat ejaculatory behavior produced by 5-HTP.
        Psychopharmacology (Berl). 1998; 137: 374-382
        • Waldinger M.D.
        • Hengeveld M.W.
        • Zwinderman A.H.
        Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study.
        Am J Psychiatry. 1994; 151: 1377-1379
        • Pattij T.
        • de Jong T.
        • Uitterdijk A.
        • et al.
        Individual differences in male rat ejaculatory behavior: searching for models to study ejaculation disorders.
        Eur J Neurosci. 2005; 22: 724-734
        • Waldinger M.D.
        Towards evidence-based drug treatment research on premature ejaculation: a critical evaluation of methodology.
        Int J Impot Res. 2003; 15: 309-313
        • Giuliano F.
        • Clement P.
        Serotonin and premature ejaculation: from physiology to patient management.
        Eur Urol. 2006; 50: 454-466
      1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th edition, text revision) (DSM-IV-TR). Washington, American Psychiatric Association; 2000.

        • Montague D.K.
        • Jarow J.
        • Broderick G.A.
        • et al.
        AUA guideline on the pharmacologic management of premature ejaculation.
        J Urol. 2004; 172: 290-294
        • Waldinger M.D.
        Overview of premature and retarded ejaculation.
        Eur Urol Today. 2005; 17: 20-22
        • 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 I—validity of DSM-IV-TR.
        J Sex Med. 2006; 3: 682-692
        • 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. 2006; 3: 693-705
        • Waldinger M.D.
        • Hengeveld M.W.
        • Zwinderman A.H.
        • Olivier B.
        An empirical operationalization study of DSM-IV diagnostic criteria for premature ejaculation.
        Int J Psychiatry Clin Pract. 1998; 2: 287-293
        • Waldinger M.D.
        • Quinn P.
        • Dilleen M.
        • Mundayat R.
        • Schweitzer D.H.
        • Boolell M.
        A multi-national population survey of intravaginal ejaculation latency time.
        J Sex Med. 2005; 2: 492-497
      2. Obuchowski N.A. Statistical methods in diagnostic medicine. Wiley series in probability and statistics. Wiley-Interscience, New York2002
        • Waldinger M.D.
        • Zwinderman A.H.
        • Olivier B.
        • Schweitzer D.H.
        Proposal for a definition of lifelong premature ejaculation based on epidemiological stopwatch data.
        J Sex Med. 2005; 2: 498-507
        • Waldinger M.D.
        • Hengeveld M.W.
        • Zwinderman A.H.
        Ejaculation-retarding properties of paroxetine in patients with primary premature ejaculation: a double-blind, randomized, dose-response study.
        Br J Urol. 1997; 79: 592-595
        • 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. 1998; 18: 274-281
        • Mendels J.
        • Camera A.
        • Sikes C.
        Sertraline treatment for premature ejaculation.
        J Clin Psychopharmacol. 1995; 15: 341-346
        • Balbay M.D.
        • Yildiz M.
        • Salvarci A.
        • Ozsar O.
        • Ozbek E.
        Treatment of premature ejaculation with sertralin.
        Int Urol Nephrol. 1998; 30: 81-83
        • Kara H.
        • Aydin S.
        • Yucel M.
        • Aqarqun M.Y.
        • Odabas O.
        • Yilmaz Y.
        The efficacy of fluoxetine in the treatment of premature ejaculation: a double-blind placebo controlled study.
        J Urol. 1996; 156: 1631-1632
        • 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. 1996; 16: 379-382
        • 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. 1998; 159: 425-427
        • McMahon C.G.
        • Touma K.
        Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies.
        J Urol. 1999; 161: 1826-1830
        • Murat Basar M.A.
        • Atan A.
        • Yildiz M.
        • Baykam M.
        • Aydoganli L.
        Comparison of sertraline to fluoxetine with regard to their efficacy and side effects in the treatment of premature ejaculation.
        Arch Esp Urol. 1999; 52: 1008-1011
        • 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. 1999; 54: 544-547
        • 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. 2004; 46: 510-516
        • Rivera P.
        • Gonzalez R.
        • Gonzalez F.
        • Storme O.
        Use of paroxetine on-demand in premature ejaculation [in Spanish].
        Actas Urol Esp. 2005; 29: 387-391