Standard Operating Procedures in the Disorders of Orgasm and Ejaculation

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Standard Operating Procedures in the Disorders of Orgasm and Ejaculation jsm_2824

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Chris G. McMahon, MBBS, FAChSHM,* Emmanuele Jannini, MD,† Marcel Waldinger, MD, PhD,‡ and David Rowland, PhD§ *Australian Centre for Sexual Health, Sydney, Australia; †University of L’Aquila, Endocrinology and Medical Sexology, Experimental Medicine, L’Aquila, Italy; ‡Leyenburg Hospital, Psychiatry and Neurosexology, The Hague, The Netherlands; §Valparaiso University, Psychology, Valparaiso, IN, USA DOI: 10.1111/j.1743-6109.2012.02824.x

ABSTRACT

Introduction. Ejaculatory/orgasmic disorders are common male sexual dysfunctions and include premature ejaculation (PE), inhibited ejaculation, anejaculation, retrograde ejaculation, and anorgasmia. Aim. To provide recommendations and guidelines of the current state-of-the-art knowledge for management of ejaculation/orgasmic disorders in men as standard operating procedures (SOPs) for the treating health care professional. Methods. The International Society of Sexual Medicine Standards Committee assembled over 30 multidisciplinary experts to establish SOPs for various male and female sexual medicine topics. The SOP for the management of disorders of orgasm and ejaculation represents the opinion of four experts from four countries developed in a process over a 2-year period. Main Outcome Measure. Expert opinion was based on grading of evidence-based medical literature, limited expert opinion, widespread internal committee discussion, public presentation, and debate. Results. PE management is largely dependent upon etiology. Lifelong PE is best managed with PE pharmacotherapy (selective serotonin reuptake inhibitors and/or topical anesthetics). The management of acquired PE is etiology specific and may include erectile dysfunction (ED) pharmacotherapy in men with comorbid ED. All men seeking treatment for PE should receive basic psychosexual education. Graded behavioral therapy is indicated when psychogenic or relationship factors are present and is often best combined with PE pharmacotherapy in an integrated treatment program. Delayed ejaculation, anejaculation, and/or anorgasmia may have a biogenic and/or psychogenic etiology. Men with age-related penile hypoanesthesia should be educated, reassured, and instructed in revised sexual techniques which maximize arousal. Retrograde ejaculation is managed by education, patient reassurance, and pharmacotherapy. Conclusions. Additional research is required to further the understanding of the disorders of ejaculation and orgasm. McMahon CG, Jannini E, Waldinger M, and Rowland D. Standard operating procedures in the disorders of orgasm and ejaculation. J Sex Med **;**:**–**. Key Words. Premature Ejaculation; Delayed Ejaculation; Anejaculation; Retrograde Ejaculation; Selective Serotonin Reuptake Inhibitor; Behavioral Therapy

Introduction

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jaculatory dysfunction is one of the most common male sexual disorders. The spectrum of ejaculatory dysfunction extends from premature ejaculation (PE), through delayed ejaculation (DE), to a complete inability to ejaculate (known as anejaculation) and includes retrograde ejaculation.

© 2012 International Society for Sexual Medicine

The Anatomy and Physiology of the Ejaculatory Response The ejaculatory reflex comprises sensory receptors and areas, afferent pathways, cerebral sensory areas, cerebral motor centers, spinal motor centers, and efferent pathways. Neurochemically, this reflex involves a complex interplay between central serotonergic and dopaminergic neurons, J Sex Med **;**:**–**

2 with secondary involvement of cholinergic, adrenergic, oxytocinergic, and gamma aminobutyric acid (GABA) neurons. Based upon functional, central, and peripheral mediation, the ejaculatory process is typically subdivided into three phases: emission, ejection (or penile expulsion), and orgasm. Emission consists of contractions of seminal vesicles (SVs) and the prostate, with expulsion of sperm and seminal fluid into the posterior urethra, and is mediated by sympathetic nerves (T10 to L2). Ejection is mediated by somatic nerves (S2–S4) and involves pulsatile contractions of the bulbocavernosus and pelvic floor muscles together with relaxation of the external urinary sphincter. Ejection also involves a sympathetic spinal cord reflex upon which there is limited voluntary control. The bladder neck closes to prevent retrograde flow; the bulbocavernosus, bulbospongiosus, and other pelvic floor muscles contract rhythmically, and the external urinary sphincter relaxes. Intermittent contraction of the urethral sphincter prevents retrograde flow into the proximal urethra [1]. Orgasm is the result of cerebral processing of pudendal nerve sensory stimuli resulting from increased pressure in the posterior urethra, sensory stimuli arising from the verumontanum, and contraction of the urethral bulb and accessory sexual organs. Many neurotransmitters are involved in the control of ejaculation, including dopamine, norepinephrine, serotonin, acetylcholine, oxytocin, GABA, and nitric oxide (NO) [2]. Of the many studies conducted to investigate the role of the brain in the development and mediation of sexual functioning, dopamine and serotonin have emerged as essential neurochemical factors. Whereas dopamine promotes seminal emission/ ejaculation via D2 receptors, serotonin is inhibitory. Serotonergic neurons are widely distributed in the brain and spinal cord and are predominantly found in the brainstem, raphe nuclei, and the reticular formation. Currently, multiple serotonin (5-hydroxytryptamine [5-HT]) receptors have been characterized, e.g., 5-HT1a, 5-HT1b, 5-HT2a, 5-HT2b, etc. [3]. Stimulation of the 5-HT2C receptor with 5-HT2C agonists results in delay of ejaculation in male rats, whereas stimulation of postsynaptic 5-HT1A receptors results in shortening of ejaculation latency [4], leading to the hypothesis that men with PE may have hyposensitivity of 5-HT2C and/or hypersensitivity of the 5-HT1A receptor [5,6]. J Sex Med **;**:**–**

McMahon et al.

PE Definition of PE There are multiple definitions of PE (Table 1). The first contemporary multivariate evidencebased definition of lifelong PE was developed in 2008 by a panel of international experts, convened by the International Society for Sexual Medicine (ISSM), who agreed that the diagnostic criteria necessary to define PE are time from penetration to ejaculation, inability to delay ejaculation, and negative personal consequences from PE. This panel defined lifelong PE as a male sexual dysfunction characterized by “. . . ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy” [7]. This definition is supported by evidence from several controlled clinical trials that suggest that 80–90% of men with lifelong PE ejaculate within 60 seconds and the remaining 10–20% within 2 minutes (Figure 1) [17,18]. This definition should form the basis for the official diagnosis of lifelong PE. It is limited to heterosexual men engaging in vaginal intercourse as there are few studies available on PE research in homosexual men or during other forms of sexual expression. Preliminary recommendations of the American Psychiatric Association’s DSM-V committee suggest a definition which parallels the definition recently adopted by the ISSM [19]. The panel concluded that there is insufficient published evidence to propose an evidenced-based definition of acquired PE (A-PE) [7]. However, recent data suggest that men with A-PE have similar intravaginal ejaculation latency times (IELTs) and report similar levels of ejaculatory control and distress, suggesting the possibility of also a single unifying definition of PE [20]. Classifications of PE In 1943, Schapiro proposed a distinction of PE into types A and B [21]. Men with type B have always suffered from a very rapid ejaculation (or short latency), whereas in type A, the rapid ejaculation develops later in life and is often associated with erectile dysfunction (ED). In 1989, these types were, respectively, referred to as lifelong (primary) and acquired (secondary) PE [22]. Over the years, other attempts have been made to identify various classifications of PE, including several that have been incorporated into PE definitions

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SOP for Ejaculatory Dysfunction Table 1

Definitions of PE

Definition

Source

A male sexual dysfunction characterized by ejaculation which always or nearly always occurs prior to or within 1 minute of vaginal penetration, and the inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personal consequences, such as distress bother, frustration, and/or the avoidance of sexual intimacy Persistent or recurrent ejaculation with minimal sexual stimulation, before, on, or shortly after penetration and before the person wishes it. The condition must also cause marked distress or interpersonal difficulty and cannot be due exclusively to the direct effects of a substance.

International Society of Sexual Medicine, 2008 [7]

For individuals who meet the general criteria for sexual dysfunction, the inability to control ejaculation sufficiently for both partners to enjoy sexual interaction manifests as either the occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required, before or within 15 seconds) or the occurrence of ejaculation in the absence of sufficient erection to make intercourse possible. The problem is not the result of prolonged absence from sexual activity. The inability to control ejaculation for a “sufficient” length of time before vaginal penetration. It does not involve any impairment of fertility when intravaginal ejaculation occurs. Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration and before the person wishes it, over which the sufferer has little or no voluntary control, which causes the sufferer and/or his partner bother or distress Ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners The man does not have voluntary, conscious control, or the ability to choose in most encounters when to ejaculate The Foundation considers a man a premature ejaculator if he cannot control his ejaculatory process for a sufficient length of time during intravaginal containment to satisfy his partner in at least 50% of their coital connections. Men with an IELT of less than 1 minute (belonging to the 0.5 percentile) have “definite” PE, while men with IELTs between 1 and 1.5 minutes (between 0.5 and 2.5 percentile) have “probable” PE (Figure 4). In addition, an additional grading of severity of PE should be defined in terms of associated psychological problems. Thus, both definite and probable PE need further psychological subclassification in nonsymptomatic, mild, moderate, and severe PE. PE is diagnosed on the basis of the pathological IELT, as measured by the stopwatch method, with a feeling of loss of voluntary control and/or distress or relational disturbances, as measured by PRO.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, DSM-IV-TR. 4th edition. Revised, 2000 [8] International Statistical Classification of Disease, 10th Edition (ICD-10), 1994 [9]

European Association of Urology. Guidelines on Disorders of Ejaculation, 2001 [10] International Consultation on Urological Diseases, 2004 [11] American Urological Association Guideline on the Pharmacologic Management of PE, 2004 [12] Metz and McCarthy, 2003 [13] Masters and Johnson, 1970 [14]

Waldinger et al., 2005 [15]

Jannini et al., 2005 [16]

IELT = intravaginal ejaculation latency time; PE = premature ejaculation; PRO = patient-reported outcome

(e.g., global vs. situational). In 2006, Waldinger proposed the existence of four PE subtypes, with different pathogenesis [23,24]. Support for this new classification is gradually developing [25,26].

Prevalence of PE Reliable information on the prevalence of lifelong and A-PE in the general male population is lacking. Confounding accurate prevalence estimates are the competing and varying definitions of PE and the manner in which prevalence data were gathered (population based, self-report, or clinician based). Local and regional variations should be considered in the context of different cultural, religious, and political influences. Additionally, prevalence may vary across different demographics, including geography, ethnicity, and social status [27]. Based on patient self-report, PE is routinely characterized as the most common male sexual complaint [28]. Prevalence data derived from patient self-report will be appreciably higher than

prevalence estimates based on clinician diagnosis utilizing the more conservative ISSM definition of PE. The following studies demonstrate the varying prevalence estimates ranging from 30% down to 3%. Data from The Global Study of Sexual Attitudes and Behaviors (GSSAB), an international survey investigating the attitudes, behaviors, beliefs, and sexual satisfaction of 27,500 men and women aged 40–80 years, reported the global prevalence of PE (based on subject selfreport) to be approximately 30% across all age groups [29,30]. Perception of “normal” ejaculatory latency varied by country and differed when assessed either by the patient or their partner [31]. A core limitation of the GSSAB survey stems from the fact that the youngest participants were aged 40 years, an age when the incidence of PE might be different from younger men [28]. Contrary to the GSSAB study, the Premature Ejaculation Prevalence and Attitude Survey found the prevalence of PE among men aged 18–70 to be 22.7% [32]. J Sex Med **;**:**–**

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Intravaginal Ejaculatory Latency Time (IELT) Figure 1 Intravaginal ejaculation latency time measured with stopwatch in 110 men with lifelong premature ejaculation, of whom 90% ejaculated within 1 minute after vaginal penetration, including 80% within 30 seconds [17].

PE in clinical practice is frequently a selfreported complaint, making it difficult to appreciate its real epidemiology. In addition, in some men/couples, PE is diagnosed on the basis of distress rather than as an objective symptom. Another problem is the relative inconstancy of the symptom in many patients. The real prevalence is difficult to assess in clinical practice [28].

Etiology of PE Historically, attempts to explain the etiology of PE have included a diverse range of biological and psychological theories. Most of these proposed etiologies are not evidence based and are speculative at best. The determinants of PE are undoubtedly complex and multivariate, with the etiology of lifelong PE different from that of A-PE. Our understanding of the neurochemical central control of ejaculation is at best rudimentary although recent imaging and electrophysiological studies have identified increased and decreased neuronal activity in several brain areas during arousal and ejaculation [2,33]. Lifelong PE. Waldinger hypothesized that lifelong early ejaculation in humans may be explained by either a hyposensitivity of the 5-HT2C and/or hypersensitivity of the 5-HT1A receptor [5]. J Sex Med **;**:**–**

Recent studies have suggested that in some men neurobiological and genetic variations could contribute to the pathophysiology of lifelong PE, as defined by the ISSM criteria, and that the condition may be maintained and heightened by psychological/environmental factors [34–36]. A-PE. A-PE may be due to (i) urological dysfunctions, for example, ED or prostatitis [37], (ii) thyroid dysfunction [38], and (iii) psychological or relationship problems [39,40]. The acquired form of PE may be cured by medical and/or psychological treatment of the underlying cause [34]. PE and Psychological or Relationship Problems. Psychological theories include the effect of early experience and sexual conditioning, anxiety, sexual technique, the frequency of sexual activity, and psychodynamic explanations [41,42]. Anxiety has been reported as a cause of PE by multiple authors and is entrenched in the folklore of sexual medicine as the most likely cause of PE despite scant empirical research evidence to support any causal role [43,44]. Several authors have suggested that anxiety activates the sympathetic nervous system and reduces the ejaculatory threshold as a result of an earlier emission phase of ejaculation [43,44].

SOP for Ejaculatory Dysfunction Hypoactive sexual desire may lead to PE, due to an unconscious desire to abbreviate unwanted penetration [41]. Similarly, diminished sexual desire can be a consequence of chronic and frustrating PE [7]. Female sexual dysfunctions (such as anorgasmia, hypoactive sexual desire, sexual aversion, sexual arousal disorders, and sexual pain disorders, as vaginismus [45]) may also be related to A-PE. PE and Comorbid ED. Recent data demonstrate that as many as half of subjects with ED also experience PE [29,32,46]. Subjects with ED may either require higher levels of stimulation to achieve an erection or intentionally “rush” intercourse to prevent early detumescence of a partial erection, resulting in ejaculation with a brief latency [16]. This may be compounded by the presence of high levels of performance anxiety related to their ED which serves to only worsen their prematurity. However, caution should be exercised in the diagnosis of comorbid ED in men with PE as 33.3% of potent men with PE confuse the ability to maintain erections prior to ejaculation and following ejaculation, record contradictory response/s to some/all questions of the Sexual Health Inventory for Men (SHIM) especially Q3 and Q4, and receive a false positive SHIM diagnosis of ED [47]. PE and Testosterone. The role of testosterone, prolactin, and other hormones in male sexual behavior and the pathogenesis of ejaculatory dysfunction have not been completely clarified. Testosterone may play a facilitatory role in the control of ejaculation [48]. It has been also reported that men with lowest quartile prolactin levels are at increased risk of metabolic syndrome, arteriogenic ED, PE, and anxiety symptoms [49]. PE and Hyperthyroidism. The majority of patients with thyroid hormone disorders experience sexual dysfunction. Studies suggest a significant correlation between PE and suppressed TSH values in a selected population of andrological and sexological patients. The 50% prevalence of PE in men with hyperthyroidism fell to 15% after treatment with thyroid hormone normalization [41,50,51]. Although occult thyroid disease has been reported in the elderly hospitalized population, it is uncommon in the population who present for treatment of PE and routine TSH screening is not indicated unless clinically indicated [52]. PE and Prostate Disease. Acute and chronic lower urogenital infection, prostatodynia, or chronic pelvic pain syndrome (CPPS) is associated with

5 ED, PE, and painful ejaculation [41,53]. Several studies report PE as the main sexual disorder symptom in men with chronic prostatitis or CPPS with a prevalence of 26–77% [41]. Prostatic inflammation and chronic bacterial prostatitis have been reported as common findings in men with both lifelong and A-PE [41,53–55]. The exact pathophysiology of the link between chronic prostatitis, ED, and PE is unknown. It has been hypothesized that prostatic inflammation may result in altered sensation and modulation of the ejaculatory reflex but evidence is lacking [51,53,56]. It has been reported that antibiotic treatment of microbiologically confirmed bacterial prostatitis in men with A-PE resulted in a 2.6-fold increase in IELT and improved ejaculatory control in 83.9% of subjects [57].

Standard Operating Procedures for the Diagnosis of PE 1) Men presenting with self-reported PE should be evaluated with a full medical/ sexual history, a focused physical examination, inventory assessment of erectile function, and any investigations suggested by these findings (level 3) Patients expect clinicians to inquire about their sexual health [58]. Often patients are too embarrassed, shy, and uncertain if sexual complaints belong in the health care professional’s (HCP’s) office [59]. Inquiry into sexual health gives patients’ permission to discuss their sexual concerns and also screens for associated health risks (e.g., cardiovascular risk and ED). Table 2 lists recommended and optional questions that patients who complain of PE should be asked [11,60]. The recommended questions establish the diagnosis and direct treatment considerations and the optional questions gather detail for implementing treatment. Finally, the committee recommends that the HCPs take a medical and psychosocial history. Current literature suggests that the diagnosis of lifelong PE is based purely on the medical history as there are no predictive physical findings or confirmatory investigations [61]. a. As differentiation of lifelong and A-PE may be difficult in either young men or men with none or few previous sexual partners and/or limited sexual experience, a physical examination is highly desirable and represents an opportunity for screening for cardiovascular or gender-specific diseases. However, in men with A-PE, a physical examination is mandatory in an effort to identify J Sex Med **;**:**–**

6 Table 2

McMahon et al. Recommended and optional questions to establish the diagnosis of PE and direct treatment [60]

Recommended questions for diagnosis Optional questions—Differentiate lifelong and acquired PE Optional questions—Assess erectile function Optional questions—Assess relationship impact Previous treatment Impact on quality of life

What is the time between penetration and ejaculation (coming)? Can you delay ejaculation? Do you feel bothered, annoyed, and/or frustrated by your PE? When did you first experience PE? Have you experienced PE since your first sexual experience on every/almost every attempt and with every partner? Is your erection hard enough to penetrate? Do you have difficulty in maintaining your erection until you ejaculate during intercourse? Do you ever rush intercourse to prevent loss of your erection? How upset is your partner with your PE? Does your partner avoid sexual intercourse? Is your PE affecting your overall relationship? Have you received any treatment for you PE previously? Do you avoid sexual intercourse because of embarrassment? Do you feel anxious, depressed, or embarrassed because of your PE?

PE = premature ejaculation

the etiology of the PE and to alleviate its possible cause [62]. The presence of ED should be evaluated either by medical history or with the assistance of a validated instrument. Laboratory or imaging investigations are occasionally required based upon the patient’s medical history. A digital prostate examination, routine in an andrological setting for all men over 40, is useful in identifying possible evidence of prostatic inflammation or infection [63]. Figure 2 is a flow chart for the management of PE [41]. 2) Self-estimation by the patient and partner of ejaculatory latency should be used to determine IELT in clinical practice (level 1) Stopwatch measures of IELT are widely used in clinical trials and observational studies of PE but have not been recommended for use in routine clinical management of PE. Despite the potential advantage of objective measurement, stopwatch measures have the disadvantage of being intrusive and potentially disruptive of sexual pleasure or spontaneity. More recently, studies have indicated that patient or partner self-report of ejaculatory latency correlates relatively well with objective stopwatch latency and might be useful as a proxy measure of IELT [64–67]. As patient self-report is the determining factor in treatment seeking and satisfaction, it is recommended that selfestimation by the patient and partner of ejaculatory latency is accepted as the method for determining IELT in clinical practice. 3) Standardized assessment measures such as validated questionnaires and patient-reported outcome (PRO) measures can be used as an J Sex Med **;**:**–**

adjunct to a full medical/sexual history and self-estimation of ejaculatory latency in the evaluation of men presenting with selfreported PE (level 1) These measures are all relatively new and were developed primarily for use as research tools. Some have shown good psychometric properties and are potentially valuable adjuncts for clinical screening and assessment. Several PE measures have been described in the literature [68–74], although only a small number have undergone extensive psychometric testing and validation. Five validated questionnaires have been developed and published to date. Currently, there are two questionnaires that have extensive databases and meet most of the criteria for test development and validation: The Premature Ejaculation Profile (PEP) and the Index of Premature Ejaculation (IPE) [68,70]. A third brief diagnostic measure, the PE diagnostic tool (PEDT), has also been developed, has a modest database, and is available for clinical use [72]. Two other measures, the Arabic and Chinese PE Questionnaires, have minimal validation or clinical trial data available and are not recommended for clinical use. PEP. A four-item, self-report measure of PE has been developed by Patrick et al. [70]. The PEP consists of single-item constructs of the following: (i) perceived control over ejaculation; (ii) satisfaction with sexual intercourse; (iii) personal distress related to ejaculation; (iv) interpersonal difficulty related to ejaculation; and (v) an index or total score. Each of the four individual items is assessed on a five-point scale, which are averaged to provide an index PE score. The measure has been

SOP for Ejaculatory Dysfunction

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Figure 2 Management algorithm for PE [41] (ED = erectile dysfunction; IELT = intravaginal ejaculation latency time; PE = premature ejaculation; PRO = patient-reported outcome).

used in observational studies and clinical trials of PE [75]. It has also been recommended for clinical use in evaluating the subjective components of the disorder. Validation studies have been performed in comparison to stopwatch measures of intravaginal latency and other PRO measures of sexual function and distress [70,75]. The scale has adequate test–retest reliability (total scale = 0.80) and moderate to strong correlations with stopwatch measured IELT. A major limitation of the scale is the lack of validated cutoff scores, which make it less suitable for use as a diagnostic or clinical screening tool. On the positive side, it is very brief and easy to administer and may be valuable for use in a clinical setting as a measure of treatment responsiveness. IPE. The IPE was developed by Althof et al. [68]. It is a 10-item self-administered questionnaire designed to evaluate sexual satisfaction, control,

and distress in men with PE. It was developed using four stages: item pool development, initial psychometric analyses, patient interviews, and final psychometric analyses. The IPE contains three factor analytically derived domains: control, sexual satisfaction, and distress. All three domains have shown adequate internal consistency and reliability, as well as known group validity in comparing men with and without PE. Convergent validity against IELT was also strong for all three domains (control [r = 0.75], sexual satisfaction [r = 0.60], and distress [r = 0.68]). The IPE has the advantages of also being relatively brief and easy to administer, although the measure is not as brief as the PEP above. It also assesses clinically relevant domains and has adequate known groups’ validity data. However, similar to the PEP, it lacks norms and diagnostic cutoffs, and has limited value as a diagnostic or screening measure for PE. J Sex Med **;**:**–**

8 PEDT. The previous two measures (PEP and IPE) are available for use as treatment change or outcome measures of PE treatment. The PEDT, in contrast, was developed specifically for use as a screening questionnaire [71,72,74]. This questionnaire is a brief, five-item measure used to screen men for potential presence of PE based on DSMIV-TR criteria of lack of control, frequency, minimal stimulation, distress, and interpersonal difficulty. Depending on the specific need, the PEP and IPE are currently the preferred questionnaire measures for assessing PE, particularly when monitoring responsiveness to treatment. Overall, these measures may serve as useful adjuncts but should not substitute for a detailed sexual history performed by a qualified clinician. 4) The ISSM definition of lifelong PE should be universally accepted as the basis for the official diagnosis of lifelong PE (level 1) The evidence suggests that the multivariate evidence-based ISSM definition of lifelong PE provides the clinician a discriminating diagnostic tool. The IELT cutoff of about 1 minute not only captures the 90% of men with PE who actively seek treatment and ejaculate within 1 minute but also affords the clinician sufficient flexibility to also diagnose PE in the 10% of PE treatment seeking men who ejaculate within 1–2 minutes of penetration. If the ISSM definition is used, men who ejaculate in <1 minute but report adequate control and no personal negative consequences related to their rapid ejaculation do not merit the diagnosis of PE. Similarly, men who have IELTs of 10 minutes but report poor control, dissatisfaction, and personal negative consequences also fail to meet the criteria for PE. 5) The ISSM definition of lifelong PE can assist the physician as a surrogate definition of A-PE. However, the patient’s report of a substantial difference between premorbid and current IELT should also be considered in the diagnosis of A-PE in men with an IELT > 2 minutes (level 3)

Standard Operating Procedures for the Treatment of PE 1) All men seeking treatment for PE should receive basic psychosexual education (level 3) Education on PE (or coaching) may also be useful in the treatment of this condition [76–79]. Such techniques may treat those aspects of PE that are J Sex Med **;**:**–**

McMahon et al. not treated with medication. They include providing information on the prevalence of PE and general population IELT to dispel myths about PE and information on enjoyable sexual activities to extend the man and his partner’s sexual repertoire, as well as strategies to address avoidance of sexual activity or unwillingness to discuss sex with his partner. These educational strategies are designed to give the man the confidence to try the medical intervention, reduce performance anxiety, and modify his maladaptive sexual scripts. 2) Inclusion of the partner in the treatment process is an important but not a mandatory ingredient for treatment success (level 3) Some patients may not understand why the clinician wishes to include the partner and some partners may be reluctant to join the patient in treatment. However, if partners are not involved in treatment, they may be resistant to changing the sexual interaction [80]. A cooperative partner can enhance the man’s self-confidence, skills, selfesteem, and sense of masculinity and more generally assist the man to develop ejaculatory control [78]. This is, in turn, likely to lead to an improvement in the couple’s sexual relationship, as well as the broader aspects of their relationship. There are no controlled studies on the impact of involving partners in treating PE. However, a review of treatment studies for ED demonstrated the important role of including a focus on interpersonal factors on treatment success [81]. 3) On-demand dapoxetine, off-label daily dosing of paroxetine, sertraline, citalopram, fluoxetine, or clomipramine, off-label ondemand dosing of clomipramine, and/or offlabel on-demand topical anesthetics, either alone or in combination with psychosexual counseling are regarded as first line treatments for lifelong PE (level 1) In 1943, Schapiro [21] described the use of topical anesthetic ointment to delay ejaculation. The use of anesthetics to diminish the sensitivity of the glans penis is probably the oldest known form of treating PE. In 1973, the first report of successful ejaculation delay by clomipramine was published [82]. However, in the 1970s and 1980s, drug treatment of PE was not used extensively. The introduction of the serotonergic tricyclic clomipramine and the selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, fluoxetine, and citalopram has revolutionized the approach to and treatment of PE. These drugs block axonal

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SOP for Ejaculatory Dysfunction reuptake of serotonin from the synaptic cleft of central and peripheral serotonergic neurons by 5-HT transporters, resulting in enhanced 5-HT neurotransmission and stimulation of postsynaptic membrane 5-HT2C receptors. Although the methodology of the initial drug treatment studies was poor, later double-blind and placebocontrolled studies confirmed the ejaculationdelaying effect of clomipramine and SSRIs. Daily Treatment with SSRIs. Daily treatment with paroxetine 10–40 mg, clomipramine 12.5–50 mg, sertraline 50–200 mg, fluoxetine 20–40 mg, and citalopram 20–40 mg is usually effective in delaying ejaculation (Figure 3) [83–88]. A meta-analysis of published data suggests that paroxetine exerts the strongest ejaculation delay, increasing IELT approximately 8.8-fold over baseline [84]. However, the use of these drugs is limited by the lack of Food and Drug Administration (FDA) and European Medicines Agency and therefore by the need to prescribe “off-label” [89]. Ejaculation delay usually occurs within 5–10 days of starting treatment, but the full therapeutic effect may require 2–3 weeks of treatment and is usually sustained during long-term use (Figure 3) [18]. Although tachyphylaxis is uncommon, some patients report a reduced response after 6–12 months of treatment. On-Demand Treatment with SSRIs. Administration of clomipramine, paroxetine, sertraline, and fluoxetine 4–6 hours before intercourse is modestly efficacious and well tolerated but is associated with substantially less ejaculatory delay than daily

treatment [90–93]. Following acute on-demand administration of an SSRI, increased synaptic 5-HT levels are down-regulated by presynaptic 5-HT1A and 5-HT1B/1D autoreceptors to prevent overstimulation of postsynaptic 5-HT2C receptors. However, during chronic daily SSRI administration, a series of synaptic adaptive processes which may include presynaptic 5-HT1A and 5-HT1B/1D receptor desensitization greatly enhances synaptic 5-HT levels, resulting in superior fold increases in IELT compared with on-demand administration [94]. On-demand treatment may be combined with either an initial trial of daily treatment or concomitant low dose daily treatment [90–92]. On-Demand Treatment with Dapoxetine. Dapoxetine is the first compound specifically developed for the treatment of PE. Dapoxetine is a potent SSRI (pKi = 8 nM), structurally similar to fluoxetine, with a pharmacokinetic profile suggesting a role as an on-demand treatment for PE [95]. Dapoxetine has a Tmax of 1.4–2.0 hours and a terminal half-life of 19 hours with a rapid decline of plasma levels to about 5% of Cmax at 24 hours, ensuring rapid absorption and achievement of peak plasma concentration with minimal accumulation [96]. Both plasma concentration and area under the curve are dose dependent up to 100 mg and are unaffected by repeated daily dosing, food, or alcohol [97–99]. Food and ethanol do not have a clinically significant effect on dapoxetine pharmacokinetics [100]. No drug-drug interactions associated with dapoxetine, including phosphodiesterase inhibitor drugs, have been reported [101].

Mean Ejaculatory Interval (min)

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Figure 3 Selective serotonin reuptake inhibitors produce ejaculatory delay within 5–10 days [83].

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No. of weeks

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10 Dapoxetine is extensively metabolized in the liver by multiple isozymes to multiple metabolites, including desmethyldapoxetine, didesmethyldapoxetine, and dapoxetine-n-oxide, which are eliminated primarily in the urine [96,102]. Although didesmethyldapoxetine is equipotent to the parent dapoxetine, its substantially lower plasma concentration, compared with dapoxetine, limits its pharmacological activity and it exerts little clinical effect, except when dapoxetine is coadministered with CYP3A4 or CYP2D6 inhibitors. Coadministration of dapoxetine and potent CYP3A4 such as ketoconazole is contraindicated. Caution should be exercised in coadministration of dapoxetine and moderate CYP3A4 inhibitors and potent CYP2D6 inhibitors such as fluoxetine. The results of two phase 2 and five phase 3 trials have been published (Table 3) [103–108]. The five randomized, placebo-controlled, phase 3 clinical trials comprised 6,081 men with a mean age of 40.6 years (range 18–82 years) from 32 countries. An analysis of pooled phase 3 data confirms that dapoxetine 30 and 60 mg increased IELT and improved PROs of control, ejaculation-related distress, interpersonal distress, and sexual satisfaction, compared with placebo. Efficacy results were similar among each of the individual trials and for a pooled analysis, indicating that dapoxetine is consistently more efficacious than placebo regardless of a subject’s demographic characteristics. Topical Anesthetics. The use of topical local anesthetics such as lidocaine and/or prilocaine as a cream, gel, or spray is well established and is moderately effective in retarding ejaculation. A recent study reported that a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine (TEMPE®, Plethora, UK) produced a 2.4-fold increase in baseline IELT and significant improvements in ejaculatory control and both patient and partner sexual quality of life [109,110]. 4) Graded levels of patient and couple counseling, guidance, and/or relationship therapy, either alone or ideally in combination with PE pharmacotherapy, should be offered as a treatment option for most men with PE (level 3) PE exerts a significant psychological burden on men, their partners, the male/partner relationship, and their overall relationship [75,111,112]. Men with PE show other negative effects, including a general negative effect associated with sexual situations and more intense feelings of embarrassment/guilt, worry/tension, and fear of J Sex Med **;**:**–**

McMahon et al. failure [40,113]. Relative to men without PE, they indicate decreased self-confidence, increased distress and interpersonal difficulty, and mental preoccupation with their condition [40,75]. Because partner satisfaction may play a greater role in PE than ED, it is not surprising that relationship dysfunction is reported as the second most common negative effect of PE [40,114]. PE is not only associated with marital discord [115], but the insecurity of men with PE about satisfying the partner also serves as an obstacle to initiating and maintaining new relationships [114,116]. Thus, the negative psychosocial impact or burden of PE provides an essential element in the characterization of PE. Even though a physiological basis for some types of PE has been suspected for years [117,118], until recently treatment options relied, quite understandably, mainly on behavioral and psychological procedures. First, psychological factors such as anxiety and negative effect have frequently been associated with sexual dysfunctions such as PE [119,120] and therefore treatment addressing such issues has represented a logically consistent approach. Furthermore, until a decade ago, few tested and well-tolerated biologically based therapeutic procedures were available for the treatment of PE. Finally, the psychological-behavioral strategies for treating PE have been at least moderately successful in alleviating the dysfunction in the short term [121–125]. Psychological interventions are designed to achieve more than simply increasing the IELT. Targeted factors focus on the man, his partner, and their relationship. Psychotherapy and behavioral interventions improve ejaculatory control by helping men/couples to the following: (i) learn techniques to control and/or delay ejaculation; (ii) gain confidence in their sexual performance; (iii) lessen performance anxiety; (iv) modify rigid sexual repertoires; (v) surmount barriers to intimacy; (vi) resolve interpersonal issues that precipitate and maintain the dysfunction; (vii) increase communication [126,127]; and (viii) come to terms with feelings/thoughts that interfere with sexual function. Present day psychotherapy for PE most often represents an integration of behavioral (e.g., the well-known start-stop and pause-squeeze methods) and cognitive approaches within a short-term psychotherapy model [13,119,122,123,128–133]. The guiding principles of treatment are to learn to control ejaculation while understanding the meaning of the symptom and the context in which it occurs.

— — — — 2

— — — — 0

— — 0

— —

— —

— — 0

— —

— —

— —

— — 9

— —

— —

— — 1

— —

— —

— —

— —

— —

— —

— —

— —

— —

38.5 23.8† 3.5

73.5 41.9†

15.5 24.4†

0.3 11.2†

38.8 6.0† 8.8

71.3 28.2†

14.7 37.9†

0.6 26.2†

36.1 12.3 1.0

69.7 22.2

15.5 42.8

0.5 30.2

18–82 DSM-IV-TR, <2 minutes by stopwatch 6,081 9–24 weeks, parallel, fixed dose None 30 mg 60 mg Placebo (N = 1,613) (N = 1,611) (N = 1,608) 0.9 0.9 0.9 † † 3.1 3.6 1.9 2.5 3.0 1.6

*P = 0.042 † P < 0.0001 vs. placebo [103–108] AE = adverse effect; DSM-IV-TR = American Psychiatric Association. Diagnostic and statistical manual of mental disorders, DSM-IV-TR. 4th edition. Revised; IELT = intravaginal ejaculation latency time

Mean baseline IELT Mean treatment IELT IELT fold increase “Good/very good” control % Baseline % Study end “Good/very good” satisfaction % Baseline % Study end “Quite a bit/extreme” personal distress % Baseline % Study end “Quite a bit/extreme” interpersonal distress % Baseline % Study end Discontinuation due to AE

18–65 DSM-IV-TR, <2 minutes by stopwatch 166 2 weeks per treatment 72 hours 60 mg 100 mg Placebo (N = 144) (N = 155) (N = 145) 1.01 1.01 1.01 † † 2.86 3.24 2.07 2.9 3.2 2.0

18–60 DSM-IV-TR, <2 minutes estimated 157 4 weeks per treatment None 20 mg 40 mg Placebo (N = 145) (N = 141) (N = 142) 1.34 1.34 1.34 † 2.22 2.72* 3.31 2.0 2.5 1.7

Phase 3 studies (pooled) Study 1–5 [105–108]

Study 1 [104]

Study 2 [103]

Phase 2 studies

Results of dapoxetine phase 2 and 3 studies

Age range (years) Inclusion criteria, IELT Number subjects Treatment period Washout period Dapoxetine dose

Table 3

SOP for Ejaculatory Dysfunction 11

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12 Although the new and often more expedient pharmacological therapies are overshadowing traditional psychological-behavioral methods in the treatment of PE, the psychological-behavioral approach remains an attractive option for several reasons. The treatment is specific to the problem, is neither harmful nor painful, is less dependent on the man’s medical history, produces minimal or no adverse side effects, and encourages open communication about sexuality in the couple which is likely to lead to a more satisfying sexual relationship [134,135], although data to support long-term efficacy are lacking [124,125]. Once the techniques have been learned and incorporated into lovemaking, PE men continue to have access to strategies that help them control their ejaculation. At the same time, there are drawbacks to the psychological-behavioral approach: it is timeconsuming, often requires substantial resources of both time and money, lacks immediacy, requires the partner’s cooperation, and has mixed (and less well-documented) efficacy [136,137]. Combining a medical and psychological approach may be especially useful in men with A-PE where there is a clear psychosocial precipitant or lifelong cases where the individual or couple’s responses to PE are likely to interfere in the medical treatment and ultimate success of therapy. Similarly, in men with PE and comorbid ED, combination therapy may also be helpful to manage the psychosocial aspects of these sexual dysfunctions. Once the man’s self-confidence and sense of control have improved, it may then be possible to reduce or discontinue the medical intervention [18].

McMahon et al.

6) Men treated with PE pharmacotherapy should be alerted to potential adverse effects (AEs) and the risk of withdrawal syndrome, advised to increase the frequency of intercourse, and reviewed after 4–6 weeks of treatment and thereafter as determined by the physician (level 1)

nondepressed PE men compared with depressed men treated with SSRIs [138]. This effect may be related to the protective action of increased oxytocin release in men with lifelong PE [5]. Neurocognitive AEs include significant agitation and hypomania in a small number of patients, and treatment with SSRIs should be avoided in men with a history of bipolar depression [139]. Systematic analysis of randomized controlled studies indicates no statistical evidence of an increased risk of suicide with SSRIs in adults [140,141]. However, an FDA meta-analysis of all pediatric randomized clinical trials of antidepressants suggested a small increase in the risk of suicidal ideation or suicide attempts in youth [141]. This effect is quite variable across SSRIs and it is not clear if that variance is a measurement error or represents a real difference between medications. Furthermore, systematic questionnaire data, epidemiological and autopsy studies, recent cohort surveys, and the negligible number of suicides that occur in youth taking antidepressants at the time of death do not support the hypothesis that SSRIs induce suicidal acts and suicide, raising concerns over ascertainment artifacts in the adverse event report method [140]. However, it would seem prudent to not prescribe SSRIs to young men aged 18 years or less and to men with a depressive disorder, particularly when associated with suicidal thoughts. Patients should be advised to avoid sudden cessation or rapid dose reduction of SSRIs which may be associated with a SSRI Withdrawal Syndrome, characterized by dizziness, headache, nausea, vomiting, and diarrhea and occasionally agitation, impaired concentration, vivid dreams, depersonalization, irritability, and suicidal ideation [142,143]. Platelet serotonin release has an important role in hemostasis [144] and SSRIs, especially with concurrent use of aspirin and nonsteroidal anti-inflammatory drugs, may be associated with increased risk of upper gastrointestinal bleeding [145,146]. Priapism is a rare AE of SSRIs and requires urgent medical treatment [147–149]. Long-term SSRI use may be associated with weight gain and an increased risk of type-2 diabetes mellitus [150].

Daily Treatment with SSRIs. AEs of daily SSRIs are usually minor, start in the first week of treatment, gradually disappear within 2–3 weeks, and include fatigue, yawning, mild nausea, diarrhea, or perspiration. Hypoactive desire and ED are infrequently reported and appear to have a lower incidence in

Dapoxetine. Across trials, dapoxetine 30 and 60 mg were well tolerated with a low incidence of severe AEs. The most frequently reported AEs were nausea, diarrhea, headache, dizziness, insomnia, somnolence, fatigue, and nasopharyngitis. Unlike other SSRIs used to treat depression, which have

5) Men with A-PE should receive etiologyspecific treatment which may also include PE pharmacotherapy (level 1)

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SOP for Ejaculatory Dysfunction been associated with high incidences of sexual dysfunction in depressed patients [151,152], dapoxetine was associated with low rates of sexual dysfunction in men with PE. Finally, dapoxetine had no effect on mood and was not associated with anxiety, akathisia, suicidality, or withdrawal syndrome. Topical Anesthetics. The use of topical anesthetics may be associated with significant penile hypoanesthesia and possible transvaginal absorption, resulting in vaginal numbness and resultant female anorgasmia unless a condom is used [153–155]. 7) Treatment outcome can be addressed in one simple, brief, and validated question known as the clinical global index of change (CGIC) (level 1) It asks patients, “Compared to before starting treatment, would you describe your premature ejaculation problem as: much worse, worse, slightly worse, no change, slightly better, better, or much better?” [156]. In the original research study, the phrase “before starting treatment” was actually “before the start of the study. Further research should document the validity of this minor wording change. In randomized, placebocontrolled, double-blind trials of dapoxetine for each category of improvement on the CGIC, the magnitude of IELT prolongation increased in concert with the CGIC rating. Additionally, significant positive correlations were noted between CGIC ratings and ejaculatory control, and sexual satisfaction and inverse correlation were noted with sexual distress. Control accounted for the greatest proportion of the variance of the CGIC. 8) Off-label daily dosing of a1-adrenoceptor antagonists, tramadol, and penile injection therapy are not recommended for the treatment of PE (level 4) Daily Treatment with a1-Adrenoceptor Antagonists. Ejaculation is a sympathetic spinal cord reflex which could theoretically be delayed by a1-adrenergic blockers. Several researchers have reported their experience with the selective a1-adrenergic blockers, alfuzosin and terazosin, in the treatment of PE. Both drugs are approved only for the treatment of lower urinary tract symptoms in men with obstructive benign prostatic hyperplasia. In a double-blind placebo-controlled study, Cavallini reported that both alfuzosin (6 mg/day) and terazosin (5 mg/day) were effective in delaying ejaculation in approximately 50% of the cases

13 [157]. Similarly, Basar et al. reported that terazosin was effective in 67% of men [158]. However, both studies were limited by the use of subjective study end points of patient impression of change and sexual satisfaction, and they did not evaluate actual ejaculatory latency. Additional controlled studies are required to determine the role of a1-blockers in the treatment of PE. On-Demand Treatment with Tramadol. Tramadol is a centrally acting synthetic opioid analgesic with an unclear mode of action which is thought to include binding of parent and M1 metabolite to m-opioid receptors and weak inhibition of reuptake of GABA, norepinephrine, and serotonin [159]. The efficacy of on-demand tramadol in the treatment of PE was recently reported [160–162]. Most studies are poorly designed open label trials with a wide range of efficacy. The only double-blind trial well-designed study demonstrates a superiority to placebo but a mediocre fold increase in IELT of 2.49, consistent with the weak serotonin reuptake inhibitor activity of tramadol [162]. The unclear safety profile and the potential for addiction discourage the use of tramadol in PE clinical practice. Intracavernous Injection of Vasoactive Drugs. Intracavernous self-injection treatment of PE has been reported but is currently without any evidencebased support for efficacy or safety [163]. 9) Off-label on-demand or daily dosing of phosphodiesterase type-5 inhibitors (PDE5is) is not recommended for the treatment of lifelong PE in men with normal erectile function. ED pharmacotherapy alone or in combination with PE pharmacotherapy is recommended for the treatment of lifelong or A-PE in men with comorbid ED (level 4) PDE5 isoenzyme inhibitors, sildenafil, tadalafil, and vardenafil, are effective treatments for ED. Several authors have reported experience with PDE5is alone or in combination with SSRIs as a treatment for PE [164–182]. The putative role of PDE5is as a treatment for PE is speculative and based only upon the role of the NO/cGMP transduction system as a central and peripheral mediator of inhibitory nonadrenergic, noncholinergic nitrergic neurotransmission in the urogenital system [183]. Although a review of 14 studies on the PDE5i drug treatment of PE has failed to provide robust empirical evidence to support a role of PDE5i in the treatment of PE with the exception of men with PE and comorbid ED [184], recent well-designed studies do support a potential J Sex Med **;**:**–**

14 role for these agents, suggesting a need for further evidence-based research [180]. 10) Selective dorsal nerve neurotomy or hyaluronic acid gel glans penis augmentation is not recommended for the treatment of PE. Surgery may be associated with permanent loss of sexual function and is contraindicated in the management of PE (level 4) Several authors have reported the use of surgically induced penile hypoanesthesia via selective dorsal nerve neurotomy or hyaluronic acid gel glans penis augmentation in the treatment of lifelong PE refractory to behavioral and/or pharmacological treatment [185–187]. The role of surgery in the management of PE remains unclear until the results of further studies have been reported. 11) Nutritional supplements containing L-tryptophane, other amino acids, or vitamins are not recommended for the treatment of PE (level 4) Multiple nutritional supplements containing L-tryptophane, vitamins, and various herbs have been recommended for the treatment of PE. However, there is not any scientific study that has investigated their use or their efficacy in the treatment of PE and they cannot be recommended. DE, Anejaculation, and Anorgasmia

Any psychological or medical disease or surgical procedure which interferes with either central control of ejaculation or the peripheral sympathetic nerve supply to the vas and bladder neck, the somatic efferent nerve supply to the pelvic floor, or the somatic afferent nerve supply to the penis can result in DE, anejaculation, and anorgasmia. As such, the causes of DE, anejaculation, and anorgasmia are manifold (Table 4).

Definition,Terminology, and Characteristics of Men with DE DE or inhibited ejaculation (IE) is probably the least common, least studied, and least understood of the male sexual dysfunctions. However, its impact is significant in that it typically results in a lack of sexual fulfillment for both the man and his partner, an effect further compounded when procreation is among the couple’s goals of sexual intercourse. DSM-IV-TR defines DE as the persistent or recurrent delay in, or absence of, orgasm after a normal sexual excitement phase during sexual J Sex Med **;**:**–**

McMahon et al. Table 4 Causes of delayed ejaculation, anejaculation, and anorgasmia Psychogenic Congenital

Anatomic causes Neurogenic causes

Infective

Endocrine Medication

Inhibited ejaculation Mullerian duct cyst Wolfian duct abnormality Prune belly syndrome Transurethral resection of prostate Bladder neck incision Diabetic autonomic neuropathy Multiple sclerosis Spinal cord injury Radical prostatectomy Proctocolectomy Bilateral sympathectomy Abdominal aortic aneurysmectomy Para-aortic lympthadenectomy Urethritis Genitourinary tuberculosis Schistosomiasis Hypogonadism Hypothyroidism Alpha-methyl dopa Thiazide diuretics Tricyclic and SSRI antidepressants Phenothiazine Alcohol abuse

SSRI = selective serotonin reuptake inhibitor

activity that the clinician, taking into account the person’s age, judges to be adequate in focus, intensity, and duration. The disturbance causes marked distress or interpersonal difficulty; it should not be better accounted for by another axis I (clinical) disorder or caused exclusively by the direct physiologic effects of a substance or a general medical condition [8]. Similarly, the World Health Organization Second Consultation on Sexual Dysfunction defines DE as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress [11]. There are no clear criteria as to when a man actually meets the conditions for DE, as operationalized criteria do not exist. Given that most sexually functional men ejaculate within about 4–10 minutes following intromission [75], a clinician might assume that men with latencies beyond 25 or 30 minutes (21–23 minutes represents about two standard deviations above the mean) who report distress or men who simply cease sexual activity due to exhaustion or irritation qualify for this diagnosis [188] (Figure 4). Such symptoms, together with the fact that a man and/or his partner decide to seek help for the problem, are usually sufficient for a DE diagnosis. Preliminary recommendations of the American Psychiatric Association’s DSM-V committee suggest a need for additional observational

15

SOP for Ejaculatory Dysfunction 100 90

Percentage of subjects

80 70 60 50 40 30 20 10

0 80 2,

0 60 2,

0 40 2,

0 20 2,

0 00 2,

0 80 1,

0 1,

60

0 40 1,

0 20 1,

0 00 1,

0 80

0 60

0 40

0 20

0

0

Intravaginal Ejaculatory Latency Time (IELT) Figure 4 Distribution of intravaginal ejaculatory latency time (IELT) values in a random cohort of 491 men with a median IELT of 5.4 minutes [188].

research as a preliminary step in the development of an evidence-based definition of DE [189]. Failure of ejaculation can be a lifelong problem or an acquired problem. It may be global and happen in every sexual encounter or intermittent or situational. Normative descriptive data from large samples of DE men have not been available, but a recent analysis identified 25% of a clinical sample suffering from lifelong DE, with the remainder reporting a secondary problem [190]. While coital anejaculation is frequently the treatment driver (especially for extremely religious individuals referred for fertility problems), men also seek treatment when distressed by their inability to achieve orgasm in response to manual, oral, or vaginal stimulation by their partner. Many men with acquired DE can masturbate to orgasm, whereas others, for multiple reasons, will or cannot. Loss of masturbatory capacity secondary to emotional or physical trauma is also seen. Approximately 75% of one clinical sample [190] could reach orgasm through masturbation, while the remainder either would not or could not.

symptomatology so indicates, investigation of such possible etiologies may be necessary.

Pathophysiology of DE A number of pathophysiologies have been associated with ejaculatory problems. These include congenital disorders as well as ones caused by trauma, infection, disease, and treatment for other disorders (Table 4). When a medical history or

Neuropathy The ability to ejaculate may be severely impaired in multiple sclerosis, diabetic autonomic neuropathy, and by spinal cord injury (Table 5) [191]. Approximately 22% of patients with an incomplete upper motor neuron lesion and almost all

Congenital Typical congenital problems include Mullerian duct obstruction, caused by failure of complete absorption of Mullerian duct remnants in the male; Wolffian duct abnormalities which may compromise vas deferens, ejaculatory duct, and SV functioning; and prune belly syndrome. Endocrine DE and anejaculation are commonly seen in men with hypothyroidism and occasionally in hypogonadal men. Iatrogenic Traumatic damage may result from prostate surgery, surgery following correction of an imperforate anus, and infection. Various pelvic cancers and their treatment (surgical or radiotherapy) may interfere with normal ejaculatory function. DE and anejaculation are reported AEs of several commonly prescribed drugs particularly SSRI antidepressants and major tranquillizers.

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16 Table 5

McMahon et al. Correlation of erection, ejaculation, and intercourse with level and severity of spinal cord injury [191]

Cord lesion Upper motor neuron lesion Lower motor neuron lesion

Complete Incomplete Complete Incomplete

Reflexogenic erections (%)

Psychogenic erections (%)

Successful coitus (%)

Ejaculation (%)

92 93 0 0

9 48 24 1

66 86 33 100

1 22 15 100

men with incomplete lower motor neuron lesions retain the ability to ejaculate. In those patients capable of successful ejaculation, the sensation of orgasm may be absent and retrograde ejaculation often occurs.

anxiety,” a factor that may contribute to DE. Specifically, anxiety surrounding the inability to ejaculate may draw the man’s attention away from erotic cues that normally serve to enhance arousal [196].

Psychological Factors Like most other sexual dysfunctions, unless a clear pathophysiology has been identified, DE may be best understood as an interaction of organic and psychogenic factors. That is, a biological set point for ejaculatory latency is affected by multiple organic and psychogenic factors in varying combinations over the course of a man’s life cycle. Appropriate assessment requires an appreciation of how these factors combine to inhibit ejaculatory response for any particular individual. Psychodynamic interpretations emphasize psychosexual development issues and have attributed lifelong DE to a wide range of conditions, including fear, anxiety, hostility, and relationship difficulties [192–195]. Masters and Johnson were the first to suggest that DE in some men might be associated with orthodoxy of religious belief [14]. In summary, delayed or absent ejaculation can be a lifelong or an acquired problem. Many psychodynamic explanations have been offered for DE and these may account for the problem in specific individual cases. More likely, men with DE derive greater arousal and enjoyment from masturbation than from intercourse, an “autosexual” orientation that may involve an idiosyncratic and vigorous masturbation style that interferes with the ability to attain orgasm [196–201]. In fact, masturbatory frequency and style may be predisposing factors for DE, as a substantial portion of men who present with coital DE report high levels of idiosyncratic masturbatory activity [197–201]. Disparity between the reality of sex with the partner and the sexual fantasy used during masturbation may inhibit sexual arousal and thus represent another contributor to DE [197,202] and, finally, the evaluative/performance aspect of sex with a partner often creates “sexual performance

Standard Operating Procedures for the Diagnosis of DE, Anejaculation, and Anorgasmia 1. Evaluation of men presenting with DE/ anejaculation should include a full medical/ sexual history, a focused physical examination, determination of serum testosterone levels, and any additional investigations suggested by these findings (level 4) Treatment should be etiology specific and address the issue of infertility in men of a reproductive age. If a man has difficulty with ejaculation or has a small volume or absent ejaculate, it should first be established whether the problem is congenital or acquired and whether organic factors are implicated. Assessment begins by reviewing the conditions under which the man is able to ejaculate, for example, during sleep, with masturbation, with partner’s hand or mouth stimulation, or infrequently with varying coital positions. The course of the problem is documented, and variables that improve or worsen performance are noted. Questions concerning the man’s ability to relax, sustain, and heighten arousal and the degree to which he can concentrate on sensations are posed [203]. If orgasmic attainment had been possible previously, the life events/circumstances temporarily related to orgasmic cessation are reviewed. The events in question maybe pharmaceutical, congenital problems, illness, trauma, or a variety of life stressors and other psychological factors, for example, following his wife’s mastectomy, the man is afraid of hurting her and therefore only partially aroused. Societal/religious attitudes that may interfere with excitement are noted, such as the spilling of seed as a sin. Finally, questions concerning the quality of the nonsexual relationship are posed and problems explored. This assessment in conjunction with appropriate

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SOP for Ejaculatory Dysfunction physical examination and laboratory results will provide understanding and determine an appropriate treatment path. Before considering a psychological/behavioral approach toward the treatment of DE, clinicians first need to exclude probable iatrogenic and pathophysiological causes. They should, for example, be alert to various medical conditions as well as medications that might delay ejaculation and, in the case of antidepressants, consider a reduction in dose or use of antidote [204]. Neuropathic damage that causes DE is usually irreversible and therefore the patient might be counseled to seek alternative methods to achieve mutual sexual satisfaction with his partner. Whether a clear pathophysiological cause is present or absent, patients might be counseled to consider lifestyle changes, including enjoying more time together to achieve greater intimacy, minimizing alcohol consumption, making love when not tired, and practicing techniques that maximize penile stimulation such as pelvic floor training [193]. Patient education regarding existing factors that can exacerbate their DE is an important first step and may represent a segue into either short- or long-term counseling. Along with a medical history, physical examination may help establish whether organic factors play a role in the DE, including whether the testicles and epididymes are normal and whether the vasa are present or absent, on each side. An endocrinopathy should be excluded with a screening morning total testosterone level and any other indicated hormonal or imaging studies. It is also important to establish whether ejaculation is retrograde or absent, with the presence of spermatozoa in urine indicating retrograde ejaculation. If the etiology is unclear, organic factors such as hemospermia may require investigation. Culture of expressed prostatic secretion and urine will define the nature of an infective process such as prostatitis [205] and urine cytology, and serum prostate-specific antigen should be assayed to exclude bladder or prostatic cancer. Ultrasound scan of the testicles and epididymes may define any local disease. Patients with ejaculatory duct obstruction usually present with infertility. Seminal analysis may simply be reported as showing azoospermia or oligozoospermia, but the characteristic biochemical changes should be sought. When vasa are absent, it is important to establish whether the condition is unilateral or bilateral. With unilateral

17 absence of the vas deferens, the urinary system must also be checked by ultrasound scanning, as coexisting renal anomalies may be present [206]. With bilateral absence or malformation of the vasa, it is essential to consider whether the anomaly may be part of a genetic defect associated with carriage of the potentially harmful cystic fibrosis chromosome anomaly [207]. In addition to the general investigation, more focused investigations may be warranted when a medical history or symptomatology suggests. These may include such procedures as imaging for ejaculatory duct obstruction, electrophysiological evaluation of neural pathways controlling ejaculation, pudendal somatosensory and motor evoked potentials, sacral reflex arc testing, and sympathetic skin responses. Figure 5 is a flow chart for the management of DE [41].

Standard Operating Procedures for the Treatment of DE, Anejaculation, and Anorgasmia 1. Treatment of DE/anejaculation should be etiology specific and may include patient/ couple psycho-education and/or psychosexual therapy, pharmacotherapy, or integrated treatment. Men/partners of reproductive age should be informed of the risk of infertility due to anejaculation following pelvic surgery and the need for sperm harvesting and assisted reproductive techniques (level 4) Psychological Strategies in the Treatment of DE Beneficial effects through psychotherapy depend on the severity of the DE and the individual’s receptiveness to engage in counseling and adhere to the counselor’s recommendations. Indeed, for DE that has its probable roots in psychological and behavioral issues, psychotherapy is probably the only effective treatment, as effective drug treatment is limited and poorly tested. The man who presents with DE for whom organic and pharmacologic causes have been eliminated requires thorough psychosexual assessment. His partner and the quality of the relationship also warrant exploration. Numerous psychotherapeutic processes are described for the management of DE or IE [14,192,208,209] and some appear to be effective, but none has been properly evaluated in largescale samples [210]. Among these strategies are the following: (i) sex education; (ii) reduction of goal-focused anxiety; (iii) increased, more genitally focused stimulation; (iv) patient role playing an exaggerated ejaculatory response on his own and J Sex Med **;**:**–**

18

McMahon et al. FAILURE OF EMISSION •Neurogenic •Metabolic •Drug Adverse Effect Disease-Specific Management

DELAYED EJACULATION ANEJACULATION ANORGASMIA NEVER

INHIBITED MALE ORGASM Psychosexual Therapy

IS THERE ORGASM?

SOMETIMES

INHIBITED MALE ORGASM Nocturnal/Masturbation Emissions Psychosexual Therapy AGE-RELATED DEGENERATION

ALWAYS

IS THERE EJACULATION?

YES

NO

ARE SPERM PRESENT IN URINE AFTER ORGASM?

NO

ASPERMIA Ejac.Duct Obstruction

YES

RETROGRADE EJACULATION Reassure/Educate Pharmacotherapy Surgery

Figure 5 Management algorithm for delayed ejaculation, anejaculation, and anorgasmia [41]

in front of his partner; (v) masturbatory retraining; and (vi) realignment of sexual fantasies and arousal strategies. Treatment strategies for DE have typically been based upon the etiologies previously described and most benefit from cooperation of the sexual partner. Successful treatment approaches typically begin by recognizing the importance of destigmatizing the dysfunction, providing appropriate sex-response education to the couple, and defusing dyadic tension that might have evolved in response to the dysfunction. For example, discussion of a potential biologic predisposition is often helpful in reducing patient and partner anxiety and mutual recriminations, while simultaneously assisting the formation of a therapeutic alliance with the HCP [190]. Most current sex therapy approaches to DE emphasize the importance of masturbation in the J Sex Med **;**:**–**

treatment of DE, with most of the focus on “masturbatory retraining” integrated into sex therapy [190,211]. Masturbation retraining is, however, only a means to an end, and the true goal of most current therapeutic techniques for DE (either lifelong or acquired) is to both provide more intense stimulation and induce higher levels of psychosexual arousal so that the man can attain orgasm within the framework of a satisfying partnered experience. A number of strategies have been utilized to achieve the end points of increased arousal and satisfaction. Men with lifelong anorgasmia (a complete lack of ejaculatory response), like their female counterparts, typically need help determining their sexual arousal preferences through self-exploration and then in communicating that knowledge to their partner. Masturbation training may use a modification of the model described by Barbach [212] for

SOP for Ejaculatory Dysfunction women. Progressing from neutral sensations to the ability to identify and experience pleasurable sensations is encouraged whether or not ejaculation should occur. Typically, self-stimulation techniques incorporating fantasy can be used to achieve incremental increases in arousal that eventually enable orgasm. Fantasy can serve the purpose of increasing arousal and blocking inhibiting thoughts that might otherwise interfere. Once the man’s ejaculatory ability is established through masturbation, the same skill set can be incorporated into sex with the partner. Although some cultures and religions forbid masturbation, temporary religious dispensation is sometimes available, especially when procreation is a goal of treatment. An important component in the treatment of any type of DE is the removal of the “demand” (and thus anxiety-producing) characteristics of the situation [208]. “Ejaculatory performance” anxiety can interfere with the erotic sensations of genital stimulation and may result in levels of sexual excitement insufficient for climax (although they may be more than adequate to maintain an erection). To reduce anxiety, treatment may include recognition of DE men’s overeagerness to please their partners, validation of (though not necessarily encouragement of) the man’s autosexual orientation, removal of stigmas suggesting hostility or withholding toward their partner, and general anxiety reduction techniques such as relaxation and desensitization. By normalizing the anorgasmia, therapy can then explore factors that increase the man’s arousal (similar to treatment of anorgasmia in women). Finally, like a previously anorgasmic woman, the man is taught to effectively communicate his preferences to his partner so that both their needs are incorporated into the sexual experience. As with counseling for other kinds of problems, men with DE may resist the recommendations of the therapist. For example, a therapeutic suggestion to temporarily discontinue masturbation may be met with resistance by the patient. In addition to suspending masturbation, the patient might be encouraged to use fantasy and bodily movements during coitus that help approximate the thoughts and sensations previously experienced in masturbation. This process is facilitated and resistance minimized when the man’s partner is supported by the practitioner and understands that the alteration in coital style is part of a series of steps designed to reach a long-term goal of coital harmony and satisfaction for them both.

19 The partner also needs to collaborate in the therapeutic process, finding ways that not only to enhance the man’s arousal but also to accept the use of erotica and various (harmless) sexual fantasies that also might be incorporated into the couple’s lovemaking. Furthermore, because interventions used in the treatment of DE may be experienced by the female partner as mechanistic (e.g., using a stepwise program) and insensitive to her sexual needs, the therapeutic challenge is to facilitate the rapport between the partners, while maintaining a therapeutic alliance with both partners and simultaneously optimizing his response to her manual, oral, and vaginal stimulation. Finally, issues surrounding reproduction/ conception may need to be addressed, as this issue is often an initial driver for treatment. If discordance exists in the couple’s reproductive goals, the practitioner must find an acceptable way to refocus the treatment, at least temporarily, on the underlying issues responsible for the discordant goals in order for DE treatment to succeed. This process may require individual sessions with the man and occasionally with the partner as well. The success of treating DE is difficult to assess from the literature [210] as the evidence on the effectiveness of various treatments is limited [137,193], and both successful and unsuccessful case reports have been cited [199,208]. Although many treatments for DE have been suggested in the psychotherapy literature [14,192,213–217], few have been subject to rigorous testing. Masters and Johnson [14] reported a low failure rate of 17.6% using a treatment combination of sensate focus, vigorous noncoital penile stimulation and modifications of intercourse technique. Other studies have reported success rates in the neighborhood of 70–80% using a variety of treatment approaches [218]. However, these analyses represent, for the most part, uncontrolled reports with treatment ranging from a few brief sessions of sex education to nearly 2 years of multiple-modality treatment in more complex multiple etiologic cases.

Drug Treatment for DE and IE Treatment of DE or IE with pharmaceuticals has met with limited success (Table 6). No drugs have been approved by regulatory agencies for this purpose, and most drugs that have been identified for potential use have limited efficacy, impart significant side effects, or are yet considered experimental in nature. In some instances, the drugs may J Sex Med **;**:**–**

20 Table 6

McMahon et al. Adjunctive drug therapy for delayed/inhibited ejaculation Dosage

Drug

As needed

Daily

Amantadine Pseudoephedrine Reboxetine Oxytocin Bupropion Buspirone Cyproheptadine Yohimbine

100–400 mg (for 2 days prior to coitus) 60–120 mg (1–2 hours prior to coitus)

75–100 mg bid or tid 4–8 mg

24 IU intranasal during coitus 75 mg bid or tid 5–15 mg bid 4–12 mg (3–4 hours prior to coitus)

only indirectly affect ejaculatory latency by affecting other components of the sexual response cycle; in other instances, the drugs have been used primarily to counter effects of other pharmaceuticals that iatrogenically induce DE or IE. Alpha-1-adrenergic receptor agonists such as as imipramine, ephedrine, pseudoephedrine, and midocrine may eventually have a role in the pharmacological treatment of IE. The antihistamine cyproheptadine, which increases cerebral serotonin levels, is anecdotally associated with the reversal of anorgasmia induced by the SSRI antidepressants, but no controlled studies are known [219–224]. These studies suggest an effective dose range of 2–16 mg, with administration on a chronic or “on-demand” basis [220]. Its sedative effects are likely to diminish its overall efficacy. Amantadine, an indirect stimulant of dopaminergic nerves both centrally and peripherally, has been reported to stimulate sexual behavior, ejaculation, and other sexual reflexes in rats [225,226]. Several authors have reported an effect for amantadine (100 mg) in the reversal of SSRI antidepressant-induced anorgasmia [220,227–231] when administered 5–6 hours before coitus. A variety of other pharmacological agents, including yohimbine, buspirone, apomorphine, quinelorane, and oxytocin, purportedly increase the likelihood of ejaculation in men with DE. For these agents, large sample studies have not been carried out and their use has been primarily experimental, limited, or anecdotal. As a result, findings are not sufficiently robust to recommend their use in the treatment of DE. Corresponding Author: Chris G. McMahon, MBBS, FAChSHM, Australian Centre for Sexual Health, Suite 2-4, Berry Road Medical Centre, 1a Berry Rd, St Leonards, Sydney, New South Wales 2065, Australia. Tel: +61 (02) 94373906; Fax: +61 (02) 99065900; E-mail: [email protected] J Sex Med **;**:**–**

5.4 mg tid

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SOP for Ejaculatory Dysfunction 89 Waldinger MD. Drug treatment of premature ejaculation: Pharmacodynamic and pharmacokinetic paradigms. Drug Discovery Today: Therapeutic Strategies 2005;2:37–40. 90 McMahon CG, Touma K. Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. J Urol 1999;161:1826– 30. 91 Strassberg DS, de Gouveia Brazao CA, Rowland DL, Tan P, Slob AK. Clomipramine in the treatment of rapid (premature) ejaculation. J Sex Marital Ther 1999;25: 89–101. 92 Kim SW, Paick JS. Short-term analysis of the effects of as needed use of sertraline at 5 pm for the treatment of premature ejaculation. Urology 1999;54:544–7. 93 Waldinger MD, Zwinderman AH, 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;46:510–5. 94 Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: The involvement of the serotonergic system. Behav Brain Res 1998; 92:111–8. 95 Sorbera LA, Castaner J, Castaner RM. Dapoxetine hydrochloride. Drugs Future 2004;29:1201–5. 96 Dresser MJ, Lindert K, Lin D. Pharmacokinetics of single and multiple escalating doses of dapoxetine in healthy volunteers. Clin Pharmacol Ther 2004;75:113. (abstract P1). 97 Dresser M, Modi NB, Staehr P, Mulhall JP. The effect of food on the pharmacokinetics of dapoxetine, a new on-demand treatment for premature ejaculation. J Sex Med 2005;3:25. abstract 37. 98 Modi NB, Dresser M, Desai D. Dapoxetine, a new on-demand treatment for premature ejaculation exhibits rapid single and multiple-dose pharmacokinetics. J Sex Med 2006;3:228. abstract P-02-162. 99 Modi NB, Dresser M, Desai D, Edgar C, Wesnes K. Dapoxetine has no pharmacokinetic or cognitive interactions with ethanol in healthy male volunteers. J Clin Pharmacol 2007;47:315–22. 100 Dresser MJ, Kang D, Staehr P, Gidwani S, Guo C, Mulhall JP, Modi NB. Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: Impact of age and effects of a high-fat meal. J Clin Pharmacol 2006;46:1023–9. 101 Dresser MJ, Desai D, Gidwani S, Seftel AD, Modi NB. Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors. Int J Impot Res 2006;18:104– 10. 102 Modi NB, Dresser MJ, Simon M, Lin D, Desai D, Gupta S. Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation. J Clin Pharmacol 2006;46:301–9. 103 Hellstrom WJ, Gittelman M, Althof S. Dapoxetine HCl for the treatment of premature ejaculation: A Phase II, randomised, double-blind, placebo controlled study. J Sex Med 2004;1(1 suppl):59. abstract 097. 104 Hellstrom WJ, Althof S, Gittelman M, Streidle C, Ho KF, Kell S, Nilson-Beijber A. Dapoxetine for the treatment of men with premature ejaculation (PE): Dose-finding analysis. J Urol 2005;173:238. abstract 877. 105 Pryor JL, Althof SE, Steidle C, Rosen RC, Hellstrom WJ, Shabsigh R, Miloslavsky M, Kell S; Dapoxetine Study Group. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: An integrated analysis of two double-blind, randomised controlled trials. Lancet 2006;368:929–37. 106 Buvat J, Tesfaye F, Rothman M, Rivas DA, Giuliano F. Dapoxetine for the treatment of premature ejaculation:

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