Review

Continuing Medical EducationNature Clinical Practice Urology (2008) 5, 93-103
doi:10.1038/ncpuro1016  
Received 26 July 2007 | Accepted 9 November 2007

Ejaculatory disorders: pathophysiology and management

Carlo Bettocchi, Paolo Verze, Fabrizio Palumbo, Davide Arcaniolo and Vincenzo Mirone*  About the authors

Correspondence *University of Naples Federico II, Department of Urology, Via Sergio Pansini 5, 80131 Naples, Italy

Email mirone@unina.it

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Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please complete the post-test.

Learning objectives

Upon completion of this activity, participants should be able to:

  1. Identify the most common ejaculatory disorder.
  2. Describe the physiology of ejaculation.
  3. Describe the diagnostic process for ejaculatory disorders.
  4. Describe treatments for premature ejaculation.
  5. Specify the recommended treatment for delayed ejaculation.

Competing interests

The authors declared no competing interests. Charles P Vega, the CME questions author, declared that he has served as an advisor or consultant to Novartis, Inc.

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Summary

Ejaculatory dysfunction (EjD) is one of the most common male sexual disorders, yet EjD is still frequently misdiagnosed or overlooked as a result of numerous patient and physician barriers. The wide spectrum of EjD ranges from premature or rapid ejaculation, through delayed ejaculation, to a complete inability to ejaculate—otherwise known as anejaculation—and includes retrograde ejaculation and painful ejaculation. Conventional algorithms for managing ejaculatory disorders are based either on an organic or psychogenic etiology, with the latter more traditionally considered the main cause. This paper reviews physiopathological, diagnostic and therapeutic aspects of ejaculation disorders, with a particular focus on the most prevalent disorder, premature ejaculation.

Review criteria

PubMed and MEDLINE were searched for relevant articles published from January 1997 to October 2007, using the terms "ejaculatory disorders", "ejaculatory disorders AND diagnostic assessment", and "ejaculatory disorders AND treatment". Of the citations identified by these searches, papers were selected on the basis of the date of publication, inclusion of a human and/or animal-based analysis and size of study sample (minimum of 10 patients). Only papers published in English have been cited in this Review.

Keywords:

anejaculation, ejaculatory dysfunction, intravaginal ejaculatory latency time, premature ejaculation, selective serotonin reuptake inhibitors

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Introduction

As has been previously established, a normal sexual response cycle comprises four interactive, nonlinear stages: desire, arousal, orgasm and resolution. In males, orgasm usually coincides with ejaculation, but represents a distinct cognitive and emotional cortical event. Ejaculatory dysfunction (EjD) is one of the most common male sexual disorders. Fertility is a major concern for younger men, while EjD can cause considerable distress to men of all ages. In a recent survey of 12,815 men aged 50–80 years, 46% reported an ejaculatory disturbance within the previous 4 weeks and 59% were particularly bothered by it, especially when occurring concomitantly with lower urinary tract symptoms.1

The wide spectrum of EjD ranges from premature or rapid ejaculation, through delayed ejaculation, to a complete inability to ejaculate—known as anejaculation—and includes retrograde ejaculation and painful ejaculation.2

Delayed ejaculation (DE), or ejaculatory insufficiency, is defined as the inhibition of the ejaculatory reflex, with absent or reduced seminal emission and impaired ejaculatory contractions, possibly occurring concomitantly with reduced or absent orgasm. Delayed ejaculation affects approximately 4% of sexually active men.3 Retrograde ejaculation, the most medically concerning disorder of sperm emission, occurs in 75% of men who have undergone transurethral resection of the prostate and, to a lesser extent, following bladder neck incision, owing to iatrogenic bladder neck incompetence in both cases.4

The most common EjD is premature ejaculation (PE).5, 6 According to the authors of a comprehensive review of the literature, PE affects 5–40% of sexually active men.7 This disorder is most frequently reported by adolescents or young adults, and affects more men from East Asia and fewer men from Middle Eastern and African countries than in other regions. The European prevalence seems to lie between that of East Asia and Middle Eastern and African countries.6

Still, epidemiological data on PE have been difficult to accrue owing to the lack of a globally accepted definition of the disorder.5 Criteria have been published that define any ejaculation occurring in 1 min, 2 min, 3 min or even 7 min from penetration, or 8–15 penile thrusts, as premature.6 Alternatively, the European Association of Urology disorders of ejaculation guidelines, published in 2004, define PE as the inability to control ejaculation for a "sufficient" length of time before vaginal penetration.8 Although there is no universally accepted meaning of a "sufficient" length of time, this should include those patients who are not able to delay ejaculation for more than a few coital thrusts, or even before vaginal penetration.8 Masters and Johnson9 have suggested that a man has PE if he is unable to delay his ejaculation until his partner is sexually satisfied in at least 50% of their sexual approaches.

The absence of a consensus medical definition for PE encourages a "patient-dependent" definition and a "patient-decided" diagnosis.6 This approach is risky, because diagnosis and possible therapy would then be based solely on subjective parameters, which are clearly influenced by culture, religion, policy, society, and the media—all aspects that greatly deviate from a medical definition.6 Hence, in 1994, Waldinger et al.10 proposed a simple objective method to define PE termed the intravaginal ejaculation latency time (IELT), which is the time from the start of vaginal intromission to the start of intravaginal ejaculation. For clinical assessment and therapeutic monitoring, this method could be considered the most objective in evidence-based sexual medicine.11

In 2000, the Diagnostic and Statistical Manual of Mental Disorders, version 4 (DSM-IV) expanded the definition of PE to be persistent or recurrent ejaculation with minimal sexual stimulation before, upon, or shortly after penetration and before the person wishes it, and noted an association with marked distress or interpersonal difficulty.12 In accordance with this definition, PE presents with three components: a short time interval between penetration and ejaculation, the inability to control ejaculation and distress for the man or for the couple.

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Physiology of ejaculation

The ejaculatory process is mainly mediated by the autonomic nervous system,13, 14 and consists of two main phases: emission and expulsion.15 Two groups of anatomical structures are specifically involved and distinguished in each phase. The organs involved in the emission phase comprise the epididymis, vas deferens, seminal vesicles, prostate gland, prostatic urethra and bladder neck. The organs participating in the expulsion phase include the bladder neck and urethra, as well as the pelvic striated muscles.15

Emission phase

During the emission phase, spermatozoa mixed with products secreted by accessory sexual glands are ejected into the posterior urethra by sequential epithelial secretion and smooth muscle cell contractions. Organs involved in this phase have a dense sympathetic and parasympathetic innervation mainly deriving from the pelvic plexus, also referred to as the inferior hypogastric plexus in humans. The nerves are situated retroperitoneally within the sagittal plane on either side of the rectum, and lie lateral and posterior to the seminal vesicles.15 The principle neurotransmitter involved in the sympathetic stimulation is norepinephrine, and is balanced by parasympathetic mediators such as acetylcholine. Results from rat studies have suggested a role for oxytocin and nonadrenergic/noncholinergic (NANC) factors, including ATP, neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and nitric oxide (NO) in ejaculation.16, 17, 18, 19 Sympathetic fibers, originating from the D10–L2 medullar center, are crucial to maintaining physiologic ejaculatory function. These nerves originate from the lumbar ganglia of the paravertebral sympathetic trunk. They pass posteriorly to the vena cava and then into the interaortocaval space (on the right side) or laterally to the aorta (on the left side). They are the principal constituents of the superior hypogastric plexus. Many surgical operations can cause an ejaculation disorder by disturbing these neuronal connections; importantly, retroperitoneal lymphadenectomy for testis cancer tends to affect young males, and has been the subject of several studies.20 The anatomosurgical concepts used to spare ejaculation function during retroperitoneal lymphadenectomy can be adopted for other retroperitoneal surgical operations that might also result in ejaculation disorders, such as wide lymphadenectomy for renal cell carcinoma or tumors of the upper urinary tract, exeresis of preaortic tumors, exeresis or disjunction of horseshoe kidney, and aortoiliac revascularization.20

Expulsion phase

During the expulsion phase, sperm is ejected from the urethra through the glans meatus. According to the commonly accepted theory, expulsion is a spinal cord reflex that occurs as the ejaculatory process reaches a 'point of no return'. During expulsion, the smooth muscle fibers of the bladder neck contract to prevent the backward flow of semen into the bladder; the pelvic floor muscles, along with the bulbospongiosus and ischiocavernosus muscles, have primary roles in this function, and display stereotypical rhythmic contractions to propel semen distally throughout the bulbar and penile urethra. During this process, the external urinary sphincter is normally relaxed.21 The bladder neck and proximal portion of the urethra, which both contain abundant smooth muscle fibers, receive dual sympathetic and parasympathetic innervation. Besides the cholinergic and noradrenergic components, the principal mediators found in these nerve terminals are NPY, VIP, and NO. The external urethral sphincter and pelvic floor striated muscles are solely regulated by the somatic nervous system, but there is no definitive evidence that a voluntary control of the expulsion phase exists in humans. Rhythmic pelvic striated muscle contractions leading to sperm expulsion are probably triggered mainly by the presence of semen in the bulbous urethra,22 although several alternative theories have been formulated and could explain the preservation of rhythmic contractions in patients who have dry ejaculations or patients who have undergone radical prostatectomy for prostate cancer.

In fact, while these stimuli might be sufficient to elicit ejaculation in experimental conditions, experimental and clinical findings do not support seminal fluid build-up as a necessary trigger.23 In a rat model, anesthetizing the urethra or decreasing seminal emission by injection of guanethidine monosulfate did not prevent the ejaculatory pattern during copulation.24 Moreover, ejaculatory motor patterns were still observed in patients after cystectomy, prostatectomy, vesiculectomy and urethrectomy.25 Likewise, ejaculatory motor patterns were not affected in male rats by removal of the seminal vesicles26 or all accessory genital glands.27 Thus, it might be possible that seminal emission contributes to the sensory stimuli that trigger ejaculation in intact, normal males, but it is not a necessary sensory stimulus. Many questions still remain unanswered as to the exact sensory mechanisms responsible for erection, emission and expulsion.23

Both experimental and clinical evidence suggests the presence of a spinal ejaculatory generator, which integrates peripheral and central stimuli and exerts both somatic and parasympathetic efferent pathways. The integrity of these spinal nuclei is necessary and sufficient for ejaculation, as demonstrated by the induction of the ejaculatory process after peripheral stimulation in animals and humans with spinal cord injuries located above these nuclei. The ability of peripheral stimuli to induce a complete human or partial rat penile ejaculation, despite the loss of reciprocal connections with supraspinal structures, implies that the spinal cord contains the complete neural machinery necessary for ejaculation.28 Studies using the expression of the protein product of the immediate-early gene c-fos as a marker of neural activation have demonstrated that some neurons in the central gray matter of the lumbar spinal cord are specifically activated following mating.29 A major breakthrough came from the identification of a population of neurons that have a pivotal role in the generation of an ejaculation.30 This population of neurons consists of cells located in lamina X and the medial portion of lamina VII of lumbar segments 3 and 4 (L3–4).30 Based on their location and thalamic projections, these particular neurons are referred to as lumbar spinothalamic cells.28

Furthermore, the spinal ejaculation generator is under the inhibitory and excitatory influences of supraspinal sites, including the nucleus paragigantocellularis, the paraventricular nucleus of the hypothalamus and the medial preoptic area.23 A modulating role for supraspinal areas in the ejaculatory threshold was confirmed by the finding that the urethrogenital reflex cannot be elicited in intact rats, but usually requires either thoracic spinal transection or a lesion within the nucleus paragigantocellularis, an area in the ventrolateral medulla in the brainstem.31 Definitive information on areas in the human brain that lead to ejaculation is sparse, although several studies using PET promise to provide further knowledge soon.

Serotoninergic control of ejaculation

Ejaculation involves cerebral sensory areas, motor centers and several spinal nuclei that are tightly interconnected, underlying a complex neurochemical modulation of the process. Amongst a wide number of neurotransmitters, including serotonin (5-HT), dopamine, oxytocin, gamma-aminobutyric acid (GABA), adrenaline, acetylcholine and NO, which have been shown to be involved in the regulation of ejaculation, 5-HT has a primary role at several levels of the neuraxis.15, 32

According to the principle outcomes of several experimental and clinical models, the overall effect of 5-HT on ejaculation is inhibitory.32, 33 Marson and McKenna31, 34 have shown that intrathecal injection of 5-HT inhibits ejaculation, while other analyses have confirmed the prolongation of ejaculation latency after central serotonin injection.35, 36 Yet, the local injection of low doses of 5-HT into the dorsal or median raphe nuclei lowers the ejaculatory threshold, which facilitates male rat ejaculatory behaviors.37 Theoretically, this particular finding is due to activated feedback systems that inhibit cell firing and decrease 5-HT levels in neuronal projections.38

Different 5-HT receptor subtypes might have an opposite action on the central command of ejaculation. Amongst the 14 structurally distinct 5-HT receptor subtypes identified to date, 5-HT1A, 5-HT1B and 5-HT2C subtypes, and perhaps 5-HT7 subtypes, have been shown to be involved in the control of the ejaculatory response. Animal studies have shown that administration of 5-HT1A-receptor agonists exerts an overall facilitating effect on ejaculation. Conversely, it has also been shown in several studies that subcutaneous administration of 5-HT1B receptor agonists (e.g. anpirtoline and TFMPP) impairs ejaculation in rats.39

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Pathophysiology of premature ejaculation

Studies have been performed to investigate the etiology and pathogenesis of PE, but clear mechanisms have yet to be defined. The pathophysiology of PE can be differentiated into five distinct areas—psychorelational, neurobiological, urological, hormonal and andrological—which, consequently, suggests five different therapeutic approaches.40

Pathogenesis from dysfunctional psychorelational concepts is the most studied cause of PE. According to this theory, distortions of beliefs and false convictions about sexuality, established in childhood as a consequence of adverse influences on sexual behavior, might lead to sexual dysfunction such as PE. During early sexual experiences PE is frequent and might even be considered normal. In men with PE, however, they might not allow themselves to receive the sensory feedback of those sensations occurring immediately before orgasm, which would enable the ejaculatory reflex to be brought under voluntary control.41 Also, anxiety (general or related to sexual performance), guilt (from a belief that sexual activity is sinful), and fear (of pregnancy, sexually transmitted diseases and/or being discovered) have frequently been suggested as causes of PE.42

Contrary to the classic psychosexual approach, Waldinger et al.43 have theorized, on the basis of animal models, that PE is not a psychological disorder but rather a neurobiological phenomenon due to chronic (genetic or acquired) central serotoninergic hypoactivity. Nevertheless, animal studies cannot be easily extrapolated to human sexual behavior, and further research is needed to clarify the role of the serotoninergic system in the pathogenesis of PE. Among peripheral neurobiological causes, major neurological disorders—such as multiple sclerosis, spina bifida and spinal cord tumors—are rare. Clinical studies have demonstrated that a short frenulum, penile hypersensitivity and reflex hyperexcitability could be important contributing factors to PE.44, 45 Nevertheless, Vanden Broucke et al.46 has demonstrated that penile sensitivity measurements do not correlate with ejaculation latency times (ELT) in men with normal sexual function; therefore, ELT variability cannot be explained by differences in penile sensitivity, at least in normal men. Moreover, the reproducible variation in ELT probably cannot be explained by differences in peripheral sensation, although this does not exclude the possibility that penile sensitivity has a role in creating a significantly lowered ejaculatory threshold in patients with PE.46

Sometimes urological or andrological disease can lead to PE. There is a high prevalence of chronic prostatitis in men with PE (56.5%), suggesting that prostatic inflammation is a predisposing condition for PE.47 In many cases PE is the only complaint presented, but patients frequently present with other sexual problems, such as erectile dysfunction (ED). It could be inferred that PE and ED share a vicious cycle, in which a man trying to control his ejaculation instinctively reduces his level of excitation (which can lead to ED), and a man trying to achieve an erection attempts to increase his excitation (which can lead to PE). In addition, many patients with ED might ejaculate early to hide the weakness of their erection.40

Recently, hyperthyroidism has been shown to be a possible promoting factor of PE.48 As the relationship between thyroid hormones and ejaculatory dysfunction is currently unknown, three possible sites of action have been hypothesized: the sympathetic nervous system, the serotoninergic system and the endocrine/paracrine system.40 In addition, thyroid hormone receptors have been identified in animal and human testes, and might also be present in other male genital tract structures that trigger ejaculation.49

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Diagnostic aspects of ejaculatory disorders

Premature ejaculation

Diagnosis of PE in clinical practice is straightforward, as it is simply based on patient self-report, clinical history, sexual history and examination findings; however, primary and acquired PE must be differentiated, which are respectively defined as experience with the problem for as long as the man has been sexually active, and development of the condition after having had previous satisfying sexual relationships without problems.

Obtaining a clinical history is crucial for identifying potential comorbidities, such as diabetes, neuropathies, traumas or urogenital infections, as well as previous surgery or drug consumption. Particular attention should be paid to micturition and ejaculation characteristics (such as nocturnal emissions, ejaculatory ability in particular circumstances, congenital or acquired disorders, and the evolution of dysfunction), as well as to the psychosexual atmosphere (education, features of the affective relationship, pre-existing psychological trauma, and previous psychological therapy).8 Owing to the absence of validated tools for diagnosing PE, the American Urological Association guidelines recommend that the diagnosis of PE be based solely upon information gathered from taking a sexual history, such as questions concerning the frequency and duration of PE, the proportion of sexual attempts with PE, the patient's relationships with specific partners, the frequency and nature of sexual activity, and the effects of PE on sexual activity and quality of life.50

Genital and rectal physical examinations are necessary to establish the absence of penile shaft abnormalities (i.e. short frenulum) or prostatic inflammation; the latter requires the performance of transrectal ultrasonography and a Meares–Stamey test. Laboratory tests are required only when there is suspicion of illicit drug use or excessive alcohol consumption.

The major objective when diagnosing PE is to quantify the length of time between penetration and ejaculation, although a multidimensional assessment of patients affected with PE, including psychosocial involvement, is also needed. Various subjective, self-report questionnaires have been proposed, and many are universally accepted and used in clinical practice. One of the most widely-used questionnaires is the Premature Ejaculation Diagnostic Tool (PEDT), a five-item tool developed to systematically apply the Diagnostic and Statistical Manual of Mental Disorders, revised version 4 (DSM-IV-TR) criteria for diagnosing the presence or absence of PE. The historical development of the DSM and the International Classification of Diseases (ICD) categorization of mental disorders have been critically reviewed. The critical reanalysis of two previous studies using the DSM-IV-TR definition of PE revealed a low, positive-predictive value for the DSM-IV-TR definition when used as a diagnostic test.51 By contrast, Symonds et al.52 confirm that the PEDT is an extensively validated self-report measure that can systematically assess DSM-IV-TR criteria to provide accurate diagnoses in patients affected with PE. Another newly developed tool for diagnosing PE has been proposed by Wang and colleagues;53 the Chinese Index of Premature Ejaculation (CIPE) is a 10-item, structured questionnaire that explores the major male sexual cycle—seemingly an ideal basis for the diagnosis of PE. Furthermore, an abridged version of the 25-item Male Sexual Health Questionnaire (MSHQ) was developed and validated (MSHQ-EjD Short Form) for assessing EjD.54 The MSHQ-EjD Short Form contains three ejaculatory function items and one ejaculation bother item; it offers excellent psychometric properties and should be a useful instrument for assessing EjD in clinical settings.

IELT, expressed in seconds or minutes, is the most widely used measurement to assess PE. A recent multinational, community-based, age-ranging study demonstrated that the distribution of the IELT was positively skewed, with a median time of 5.4 min and a range of 0.55–44.1 min. The differences between the men of the five different countries were explored; for all the men considered, the median IELT values were independent of condom usage. In countries excluding Turkey, the median IELT values were also independent of circumcision status.55

IELT is usually measured with a stopwatch operated by the female partner, but owing to the wide influences of psychosocial factors and cultural backgrounds, an objective evaluation is often lacking. A novel apparatus has been designed and validated to collect electronic data on IELT, called the Sexual Assessment Monitor (SAM). Dinsmore et al.56 showed that the SAM is able to measure effectively and safely the time to ejaculation from the start of vibration in healthy volunteers and men with PE. The authors concluded that the SAM has the potential to become the gold standard for the diagnosis of PE, as well as in the design of clinical trials.

Neurophysiologic tests, such as pudendal nerve somatosensory evoked potentials, bulbocavernosus (BC) reflex and BC perineal motor evoked potentials, have been recently assessed for use in the investigation of the somatic sensory and motor function of the genital area in patients presenting with primary PE. Neither an increased speed of conduction along the pudendal sensory pathway nor an increased cortical representation of the sensory stimuli from the genital area—such as hyperexcitability of the BC reflex—were confirmed in successive studies. Despite great initial interest in this area, an electrophysiologic approach by itself does not seem sufficient to identify the cause of primary PE.57

Delayed ejaculation and anejaculation

Although no clear criteria exist, given that most sexually functional men ejaculate within about 3–8 min following intromission, men with latencies beyond 20–30 min and consequent distress or men who simply cease sexual activity due to exhaustion or irritation qualify for a diagnosis of delayed ejaculation.58

The diagnostic evaluation of delayed ejaculation or anejaculation focuses on finding potential physical causes and specific psychological or acquired causes of the disorder. A medical examination and patient history are crucial, as these might uncover physical anomalies, pathophysiologies and/or iatrogenically induced conditions (e.g. treatment with antihypertensive, antipsychotic or antidepressant drugs, surgical procedures such as retroperitoneal lymphadenectomy or aortoiliac or colorectal surgery) associated with delayed or absent ejaculation. Particular attention should be given to identifying reversible urethral, prostatic, epididymal and/or testicular infections. Evaluation typically begins by differentiating this sexual dysfunction from other sexual problems (e.g. pain causing interruption of intercourse), and by reviewing the conditions under which the patient is able to ejaculate (e.g. during sleep, with masturbation, with manual or oral stimulation). Generally, a complete evaluation should identify all possible predisposing, precipitating and maintaining factors for the dysfunction, such as issues of religiosity, coital and masturbatory patterns and/or performance anxiety.

Retrograde ejaculation

Often, a diagnosis of retrograde ejaculation can be made by taking an accurate history of previous surgical procedures and drug consumption. Retrograde ejaculation can be confirmed by demonstrating sperm presence in postcoital urine.8 A differential diagnosis should be pursued for patients who present with absent or low-volume ejaculates (such as anejaculation, obstruction of an ejaculatory duct or seminal vesicle, or congenital anomalies of the accessory sex organs), with a complete physical examination and transrectal ultrasonography.

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Treatment of ejaculatory disorders

Premature ejaculation

The evolution of PE therapy has been influenced by new knowledge on physiology and etiology, and now includes behavioral, psychological and pharmacological therapies.

Currently, the pharmacological management of PE utilizes systemic or topical medications, either taken as needed or on a regular schedule. Apart from a novel agent, dapoxetine hydrochloride, the other remedies for PE are used in an off-label manner, as they were originally developed for the treatment of other pathologies but were secondarily found to delay ejaculation.

Among the various agents investigated for the oral treatment of PE, selective serotonin reuptake inhibitors (SSRIs) have demonstrated a variable efficacy compared to placebo.50 SSRIs are currently indicated as antidepressants, but citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline have also shown benefit in delaying ejaculation. In a meta-analysis of all treatment studies for PE, the majority of trials were found to lack an adequate design; only eight (18.5%) of the studies were performed according to the established evidence-based medicine criteria.59

The numerous trials studying the use of SSRIs for the management of PE have also evaluated daily versus on-demand dosing; however, the American Urological Association guidelines panel was not able to recommend a preferred dosing regimen and expressed a particular concern about the adverse-effect profiles of the various agents.50

According to results from placebo-controlled studies, daily treatment with sertraline, paroxetine, fluoxetine60 or clomipramine61 could yield safe benefits for men with PE. Above all, daily use of paroxetine has been demonstrated to yield the strongest ejaculatory delay within 5–10 days: the group with baseline IELT <1 min reported a 6.5-fold increase, while a 7.2-fold increase was observed in the group with baseline IELT of 1–3 mins.11 During treatment with SSRIs, adverse effects are usually mild to moderate and include fatigue, yawning and nausea.60 The loss of libido, ED, or significant agitation are rarely reported. The major contraindication for the daily use of SSRIs is the presence or a reported history of bipolar depression.

Waldinger et al.62 evaluated the preference of daily versus on-demand use of medication for PE in a group of 88 men with lifelong PE. Seventy one of the group (81%) preferred taking their medication daily; this result did not change after the patients were given the standard information about efficacy and adverse effects.62

On-demand administration of SSRIs 4–6 h before sexual intercourse is reported to be efficacious and well tolerated, but it is associated with a smaller delay in IELT than seen with daily administration. McMahon and Touma63 examined two placebo-controlled, crossover trials that investigated the effectiveness of paroxetine administered on a need-to-use basis. A significant IELT increase was registered after 3–4 weeks of use (P <0.001). On-demand clomipramine use has yielded greater increases in IELT than commonly used SSRIs. Waldinger and colleagues64 compared as-needed paroxetine to as-needed clomipramine with a stopwatch assessment in a randomized study. Paroxetine showed a 1.4-fold increase in IELT (95% CI 1.22–1.63), in contrast with a 4.0-fold increase when clomipramine was taken (95% CI 3.26–5.02); however, an elevated incidence of adverse effects, such as fatigue, sleepiness, dry mouth, tremor, yawning, loose stools, dizziness and headache, was reported after daily administration of both drugs.

Several rapidly acting and short half-life SSRIs are currently being studied for the treatment of PE. Oral dapoxetine hydrochloride is currently being considered for approval as the first pharmaceutical therapy developed with a specific indication for PE. In a 2007 double-blind, placebo-controlled trial, 212 potent men with PE were randomly assigned to receive either 30 mg oral dapoxetine twice daily or placebo.65 At the end of a 12-week treatment course, the dapoxetine group showed a 2.9-fold increase in mean IELT (95% CI 1.84–4.16). Significant increases were also observed in the mean weekly intercourse episodes and the mean intercourse satisfaction domain values, scored by the International Index of Erectile Function (IIEF) tool. Compared with placebo, dapoxetine use resulted in moderately prolonged IELTs and improved intercourse satisfaction, but lacked long-term benefits following discontinuation of the treatment. In a previous study, Pryor and colleagues66 assessed the efficacy of dapoxetine in two 12-week, randomized, double-blind, placebo-controlled, phase III trials of identical design. Men with moderate to severe PE received placebo, 30 mg dapoxetine or 60 mg dapoxetine as needed 1–3 h before sexual intercourse. Both dosages of dapoxetine significantly prolonged IELT compared with placebo (P <0.0001), with mild adverse effects.

A variety of phosphodiesterase (PDE)-5 inhibitors have been investigated, alone or in combination with SSRIs, for the management of PE. Potentially favorable effects supporting the use of PDE-5 inhibitors include central targeting and the resultant reduction in sympathetic tone and peripheral relaxation of smooth muscles.67 NO-mediated PDE-5 effects can thus target smooth muscle cells surrounding the vas deferens, seminal vesicles and prostate, improving the ejaculatory latency time.68

A multicenter, double-blind study was conducted with flexible doses (50–100 mg) of sildenafil in men with lifelong PE; a second group tested a single dose of 100 mg of sildenafil or placebo, taken 1 h before vibrotactile stimulation.67 Patients who received sildenafil reported increases in ejaculatory control and overall sexual satisfaction; however, the increased change in IELT did not reach statistical significance. Other studies investigated the use of combination therapies. Mattos and Lucon69 tested the use of tadalafil and the slow-release SSRI fluoxetine, alone or in combination therapy. Improved IELTs were obtained with the use of the agents in combination, compared with either single treatment. The efficacy of another PDE-5 inhibitor, vardenafil, was tested and compared with the SSRI sertraline; in men with primary or secondary PE, use of vardenafil resulted in longer IELTs than sertraline use.70

An alternative to oral medication is the use of topical agents to treat one of the supposed causes of PE—hypersensitivity of the penis. This approach involves applying local anesthetics in cream, gel or spray formulations in order to decrease penile sensitivity. Busato and colleagues71 designed a double-blind, randomized, placebo-controlled study to assess the use of lidocaine–prilocaine solution in 42 men with PE. A significant increase in mean IELT (P <0.001) was reported in the lidocaine–prilocaine group (from 1.49 to 8.45 min) compared with in the placebo group (from 1.67 to 1.95 min). With the use of local anesthetic, formulated as a cream, spray or gel, no systemic adverse effects have been reported; topical adverse effects might include skin burning, numbness, pain and irritation. The occurrence of other sexual problems, such as sexual dysfunction, is rarer.71, 72

Psychological treatment for PE has been proposed, with the aim of prolonging IELT and thus improving the sexual relationship between the patient and his partner. Several studies of psychotherapies have been reported, but there is a dearth of well-designed and controlled trials. Behavioral training techniques, including the stop-and-start and squeeze methods, are currently used by sexologists. The former was initially described by Masters and Johnson,9 and begins with manual autostimulation. After achievement of good arousal control by the man, the partner becomes involved with manual stimulation and then with sexual intercourse. The squeeze technique is similar to the aforementioned approach, except that when the stimulation is stopped, the penis is squeezed with the fingers.73 Although a good short-term success rate has been reported, behavioral techniques have never been studied in appropriate trials and tend to lose their efficacy over the long term.74

Some authors have tried to induce a permanent penile hypoesthesia by surgical selective dorsal nerve neurectomy. This surgical procedure has also been compared with hyaluronic acid gel injection, which can potentially block nerve receptors for tactile stimuli.75 No significant additive effect has been observed when injections and neurectomy are combined, but both individual treatments significantly prolong postoperative IELT.

Delayed ejaculation and anejaculation

Men suffering from delayed or inhibited ejaculation, when organic or pharmacologic causes are excluded, can benefit from a psychological approach. Preliminary psychosexual counseling is required before the psychotherapist can choose a therapy. Several approaches have been described: sex education, reduction of goal-oriented anxiety, increased and more genitally focused stimulation, and patient role-playing of an exaggerated ejaculatory response on his own and in front of his partner. In this field the literature is difficult to evaluate, as most authors report only a small series of cases with seemingly exaggerated results.76

A variety of drugs have been suggested to induce ejaculation, but no placebo-controlled studies have been published. Cyproheptadine, a serotonin-receptor antagonist, as well as several dopaminergic agents such as amantadine, yohimbine and apomorphine, are a few of the medications proposed but with variable and controversial results.

In order to achieve fertility for a patient who experiences anejaculation, sperm retrieval is possible via vibrostimulation.8 Vibrostimulation requires an intact lumbosacral spinal cord segment (above T10); if this method is not successful, electroejaculation, in which the periprostatic nerves are stimulated by a probe inserted into the rectum (generally under anesthesia), might be of benefit. If ejaculation does not occur using the aforementioned techniques, surgical sperm retrieval is the treatment of choice.

Retrograde ejaculation

When a spinal cord injury, urethral anomalies or drug consumption is excluded, men suffering from retrograde ejaculation can benefit from a pharmacological treatment.8 For example, imipramine, ephedrine sulfate and desipramine (chlorpheamine and phenylpropanalamine) have been found to improve bladder neck closure.77 Sperm collection from the urine is considered in cases of drug failure, contraindication for pharmacologic management, spinal cord injuries, or when other medications that induce retrograde ejaculation cannot be suspended.8

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Conclusions

Neuropharmacological studies and animal research have contributed to an improved understanding of the neurobiology of ejaculation and the possible causes of ejaculatory disorders. Etiological treatments of underlying pathologies should be discussed with patients and offered as first-line therapies. SSRIs and topical anesthetic creams can provide good efficacy in treating PE, even if a clear understanding of the etiology of lifelong PE is lacking. Sperm retrieval techniques should be considered for patients with anejaculation or retrograde ejaculation who have associated infertility problems.

Key points

  • Ejaculatory dysfunction is one of the most common male sexual disorders, but is still frequently misdiagnosed
  • The most common ejaculatory dysfunction is premature ejaculation (PE), which affects 5–40% of sexually active men
  • Ejaculation involves cerebral sensory areas, motor centers and several spinal nuclei that are tightly interconnected
  • Diagnosis of PE in clinical practice is straightforward, as it is simply based on patient self report, clinical history, sexual history and examination findings
  • The major objective when diagnosing PE is to quantify the length of time between penetration and ejaculation, although a multidimensional assessment of patients affected with PE, including psychosocial involvement, is also needed
  • Selective serotonin reuptake inhibitors and topical anesthetic creams can provide good efficacy for treating PE, even if a clear understanding of the etiology of lifelong PE is lacking

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Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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