Disorders of Ejaculation: An AUA/SMSNA Guideline (2020)
To cite this guideline:
- Shindel AW, Althof SE, Carrier S et al: Disorders of Ejaculation: An AUA/SMSNA Guideline. J Urol 2022; https://doi.org/10.1097/JU.0000000000002392.
Español translated guideline courtesy of Sociedad Colombiana de Urologia (SCU) [pdf]
Alan W. Shindel MD, Stanley E. Althof, Ph.D., Serge Carrier, MD, Roger Chou, MD, FACP, Chris G. McMahon, MD, John P. Mulhall, MD, Darius A. Paduch, MD, Ph.D., Alexander W. Pastuszak, MD, Ph.D., David Rowland, Ph.D., Ashely H. Tapscott, MD , Ira D. Sharlip MD.
Ejaculation and orgasm are distinct but simultaneous events that occur with peak sexual arousal. It is typical for men to have some control over the timing of ejaculation during a sexual encounter. Men who ejaculate before or shortly after penetration, without a sense of control, and who experience distress related to this condition may be diagnosed with Premature Ejaculation (PE). There also exists a population of men who experience difficulty achieving sexual climax, sometimes to the point that they are unable to climax during sexual activity; these men may be diagnosed with Delayed Ejaculation (DE). While up to 30% of men have self-reported PE, few of these men have an ejaculation latency times (the time between penetration and ejaculation) of less than two minutes, making the actual prevalence of clinical PE and DE less than 5%.1, 2 Regardless, the experience of many clinicians suggest that the problem is not rare and can be a source of considerable embarrassment and dissatisfaction for patients. Data on the prevalence of DE are more limited, but a proportion of epidemiological studies report that men have difficulty achieving orgasm.3 Disturbances of the timing of ejaculation can pose a substantial impediment to sexual enjoyment for men and their partners. The understanding of the neurobiological phenomena that comprise ejaculation and orgasm is limited. A number of psychological health, behavioral, and pharmacotherapy options exist for both PE and DE; however, none of these pharmacotherapy options have achieved approval from the United States Food and Drug Administration and their use in the treatment of PE is considered off-label. The role of the clinician in managing PE and DE is to conduct appropriate investigation, to provide education, and to offer available treatments that are rational and based on sound scientific data. The Panel recommends shared decision-making as fundamental in the management of disorders of ejaculation; involvement of sexual partner(s) in decision making, when possible, may allow for optimization of outcomes.
The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence–based Practice Center. Scoping of the report and review of the final systematic review to develop guideline statements was conducted in conjunction with the Disorders of Ejaculation Panel. A research librarian conducted searches in Ovid MEDLINE (1946 to March 1, 2019), the Cochrane Central Register of Controlled Trials (through January 2019) and the Cochrane Database of Systematic Reviews (through March 1, 2019). Searches of electronic databases were supplemented by reviewing reference lists of relevant articles. An updated literature search was conducted on September 5, 2019.
- Lifelong premature ejaculation is defined as poor ejaculatory control, associated bother, and ejaculation within about 2 minutes of initiation of penetrative sex that has been present since sexual debut. (Expert Opinion)
- Acquired premature ejaculation is defined as consistently poor ejaculatory control, associated bother, and ejaculation latency that is markedly reduced from prior sexual experience during penetrative sex. (Expert Opinion)
- Clinicians should assess medical, relationship, and sexual history and perform a focused physical exam to evaluate a patient with premature ejaculation. (Clinical Principle)
- Clinicians may use validated instruments to assist in the diagnosis of premature ejaculation. (Conditional Recommendation; Evidence Level: Grade C)
- Clinicians should not use additional testing for the evaluation of a patient with lifelong premature ejaculation. (Conditional Recommendation; Evidence Level: Grade C
- Clinicians may utilize additional testing, as clinically indicated, for the evaluation of the patient with acquired premature ejaculation. (Conditional Recommendation; Evidence Level: Grade C)
- Clinicians should advise patients that ejaculatory latency is not affected by circumcision status. (Conditional Recommendation; Evidence Level: Grade C)
- Clinicians should consider referring men with premature ejaculation to a mental health professional with expertise in sexual health. (Moderate Recommendation, Evidence Level: Grade C)
- Clinicians should recommend daily SSRIs; on demand clomipramine or dapoxetine (where available); and topical penile anaesthetics as first-line pharmacotherapies in the treatment of premature ejaculation. (Strong Recommendation; Evidence Level: Grade B)
- Clinicians may consider on-demand dosing of tramadol for the treatment premature ejaculation in men who have failed first-line pharmacotherapy. (Conditional Recommendation; Evidence Level: Grade C)
- Clinicians may consider treating men with premature ejaculation who have failed first-line therapy with α1-adrenoreceptor antagonists. (Expert Opinion)
- Clinicians should treat comorbid erectile dysfunction in patients with premature ejaculation according to the AUA Guidelines on Erectile Dysfunction. (Expert Opinion)
- Clinicians should advise men with premature ejaculation that combining behavioral and pharmacological approaches may be more effective than either modality alone. (Moderate Recommendation; Evidence Level: Grade B)
- Clinicians should advise patients that there is insufficient evidence to support the use of alternative therapies in the treatment of premature ejaculation. (Expert Opinion)
- Clinicians should inform patients that surgical management (including injection of bulking agents) for premature ejaculation should be considered experimental and only be used in the context of an ethical board-approved clinical trial. (Expert Opinion)
- Lifelong delayed ejaculation is defined as lifelong, consistent, bothersome inability to achieve ejaculation, or excessive latency of ejaculation, despite adequate sexual stimulation and the desire to ejaculate. (Expert Opinion)
- Acquired delayed ejaculation is defined as an acquired, consistent, bothersome inability to achieve ejaculation, or an increased latency of ejaculation, despite adequate sexual stimulation and the desire to ejaculate. (Expert Opinion)
- Clinicians should assess medical, relationship, and sexual history and perform a focused physical exam to evaluate a patient with delayed ejaculation. (Clinical Principle)
- Clinicians may utilize additional testing as clinically indicated for the evaluation of delayed ejaculation. (Conditional Recommendation; Evidence Level: Grade C)
- Clinicians should consider referring men diagnosed with lifelong or acquired delayed ejaculation to a mental health professional with expertise in sexual health. (Expert Opinion)
- Clinicians should advise men with delayed ejaculation that modifying sexual positions or practices to increase arousal may be of benefit. (Expert Opinion)
- Clinicians should suggest replacement, dose adjustment, or staged cessation of medications that may contribute to delayed ejaculation in men with delayed ejaculation. (Clinical Principle)
- Clinicians should inform patients that there is insufficient evidence to assess the risk-benefit ratio of oral pharmacotherapy for the management of delayed ejaculation. (Expert Opinion)
- Clinicians may offer treatment to normalize serum testosterone levels in patients with delayed ejaculation and testosterone deficiency. (Expert Opinion)
- Clinicians should treat men who have delayed ejaculation and comorbid erectile dysfunction according to the AUA Guidelines on Erectile Dysfunction. (Expert Opinion)
- Clinicians should counsel patients with delayed ejaculation that no currently available data indicate that invasive non-pharmacological strategies are of benefit. (Expert Opinion)
It is typical for men to be able to exert at least partial control of if and when they ejaculate during partnered sexual encounters and masturbation.4, 5 If a man does not feel that he has control of when ejaculation occurs, and if there is distress on the part of the man or his sexual partner(s), either premature ejaculation (PE) or delayed ejaculation (DE) may be present. The specific diagnosis is determined by whether ejaculation occurs early, late, or not at all.6
Disorders of the timing of ejaculation can pose a major impediment to sexual satisfaction for both men and their partners. In the most extreme cases, an ejaculatory disorder may lead to relationship stress or marked trepidation about starting new relationships for men afflicted with the condition.6, 7
Both PE and DE are poorly understood and difficult to define. Although the reported prevalence of clinical PE and DE is less than 5%,2, 7 the experience of many clinicians who see patients for sexual problems suggests that these problem are not at all rare. The perception of rarity may stem from the frequency with which other disabling disorders of sexual function (primarily erectile dysfunction [ED]) are present in men with comorbid disruption of ejaculation.3
The understanding of the neurophysiology of ejaculation and orgasm remains limited. Biomedical interventions for treatment of conditions that alter ejaculatory latency and control are scant. Although few such treatments have achieved regulatory approval, a number of interventions can be considered for management of distressing disruptions of ejaculation latency time ([ELT], defined as the time between penetration and ejaculation).2, 6 Education and referral to colleagues with experience in the psychological health evaluation and treatment of sexual problems are essential elements of care for these patients.8
Sexual Response Cycle
The sexual response cycle in men is conceptualized as a linear process of increasing sexual excitement, starting with desire and followed by arousal, climax, and resolution. Under normal circumstances, sexual climax in men consists of two distinct physiological events. The first of these is orgasm, a sensation of intense pleasure, relaxation, or intimacy that accompanies peak sexual arousal. The second is ejaculation, antegrade expulsion of semen from the urethra. These events are typically simultaneous and the terms are often used interchangeably in the biomedical literature. However, these are distinct physiological processes4, 5 that may occur, or not occur, independently.
Ejaculation is triggered by integration of tactile (e.g., sensation from genital or other peripheral nerves) and non-tactile (e.g., sexually arousing audio and visual inputs) stimuli in the brain. At some set point of arousal, a centrally-mediated action potential is triggered leading to ejaculatory and/or orgasmic inevitability.9 Although ejaculation occurs in the pelvis, central nervous system (CNS) involvement plays a critical role. Data from animals, and more recently humans, has indicated the presence of galaninergic neurons arranged in columns within the central spinal cord.10 Lesion of these structures is strongly associated with ejaculatory failure; it is likely that these neurons are responsible for integrating stimuli from peripheral and cerebral sources and triggering the ejaculatory reflex. Some experts have described this structure as the “spinal ejaculation generator” (SEG).10
Ejaculation consists of two distinct phases. The first of these is emission, a centrally-mediated action characterized by closure of the bladder neck and contraction of smooth muscles throughout the seminal tract (mediated by the sympathetic nervous system). The emission phase also includes secretion of seminal fluid into the proximal urethra, a process mediated by the sympathetic nervous system with some possible involvement of the parasympathetic nervous system.4, 5 The fluid content of semen is derived primarily from the seminal vesicles and prostate, with small contributions from the bulbourethral glands and from spermatozoa transported from the epididymis via the vas deferens.5 The second phase is ejection, a reflex driven by the somatic nervous system, specifically the pudendal nerve. Ejection is characterized by repeated contractions of the bulbospongiosus and ischiocavernous muscles leading to forceful expulsion of seminal fluid from the urethral meatus.4, 5 A cluster of motor neurons in spinal segments S2-4 (“Onuf’s nucleus”) appears to be of particular import for control of the striated muscles of the pelvis.5
Normal antegrade ejaculation relies heavily on the normal function of the prostate and bladder neck. Medical and surgical interventions that alter function of the prostate and/or bladder neck often have noticeable and bothersome effects on ejaculation. Specific examples include decreased ejaculate volume and force in men using alpha blockers or 5-alpha reductase inhibitors for management of benign prostatic hyperplasia (BPH).11 Surgical interventions for BPH tend to cause pronounced and difficult to resolve alterations in ejaculatory function.12 A number of novel procedural approaches to BPH have been developed due in part to dissatisfaction with ejaculatory outcomes associated with conventional surgical BPH treatments.13 Surgical removal of the prostate and seminal vesicles for prostate cancer typically results in marked reduction or complete absence of ejaculation as these organs are responsible for the vast majority of seminal volume. Radiation therapy for prostate cancer is also commonly associated with loss of antegrade ejaculation.14 Disruption of ejaculation is associated with changes in subjective experience of orgasm for some men.
The act of ejaculation has important connotations for many men, aside from its association with orgasmic pleasure and necessity for procreation. Loss or anomaly of ejaculation may lead to a diminished sense of masculinity and disruption of pleasure from orgasm for many men.15 A significant proportion of men specifically eroticize semen and are likely to be perturbed by disruption of the ejaculatory process.16, 17 Although published data are scant, female sexual partners of men may endorse that at least some of their sexual enjoyment is derived from their partner’s climax,18 however few women specifically prioritize ejaculation itself as an essential element of their sexual satisfaction.18 Ejaculation may be of greater priority in men who have sex with men (MSM).17
Orgasm is a transient neurological state characterized by intense feelings of pleasure, relaxation, and intimacy. There is tremendous variability in the subjective experience of orgasm between persons and within a given person at different times. Orgasm is typically experienced at peak sexual arousal and is followed in men by a refractory period during which arousal and sexual climax are not possible.19 The duration of the refractory period tends to become longer with increasing age. The quality and intensity of orgasm may be influenced by a variety of factors that are incompletely understood.
Orgasm is mediated by and experienced in the brain, whereas ejaculatory reflexes are mediated by the putative SEG, making the subjective experience of orgasm an integration of numerous brain centers. The bulk of existing data on the involvement of the CNS in orgasm is derived from rodents studies. Brain regions thought to be intimately involved in central integration of stimuli germane to ejaculatory response include the stria terminalis, the posterodorsal area of the medial amygdala, and the parvicellular part of the supraparafascicular thalamus. Excitatory pathways include projections from the medial pre-optic area to the paraventricular hypothalamic nucleus and lateral hypothalamic neurons, both of which connect to the SEG. The ventral medulla appears to exert an inhibitory effect on the SEG.5
In general, dopaminergic and oxytocinergic activation stimulates ejaculation and orgasm whereas serotonergic and gamma-aminobutyric acid (GABA)-ergic activation opposes ejaculation and orgasm. Agonists of opioid receptors, principally mu subtypes, are also associated with impairment of ejaculatory and orgasmic response. Specific receptors may have actions that differ (e.g., stimulation of certain serotonergic receptors in the spinal cord may promote ejaculation and orgasm).5
Orgasm is also a neuroendocrine process. Experimental and observational data in animals and humans indicate that androgens are necessary for at least the initial maturation of sexual, including ejaculatory, reflexes.20-22 Evidence in support of this is derived from studies of female and male cadavers. Male cadavers had a greater density of galaninergic neurons in the L3 and L4 spinal segments as compared to female cadavers, suggesting a sexually dimorphic developmental pathway likely mediated by differential exposure to androgens.10 These same neurons, elements of the putative SEG, are thought to be essential to the ejaculatory process as evidenced by frequency of failure to ejaculate in response to penile vibratory stimulation in men with L3-5 spinal cord injury.10
Serum testosterone (T) levels do not represent peripheral action of T in the tissues, where T acts. Variations in androgen receptor function (e.g., number of CAG repeats), intracellular trafficking of T bound to the androgen receptor, and the balance among modulators of T receptors determine the final action of T within target tissues. T action in the CNS is carried out by nuclear receptors and possibly by non-nuclear G-protein coupled receptors. It is plausible that our gaps in knowledge about modulatory and individualized factors controlling androgens' function impair our ability to link T levels and ejaculatory function convincingly.23
A common cause of disruption in ejaculation or orgasm is failure of the earlier elements of sexual response (e.g., lack of sexual desire and/or ED leading to inadequate genital and subjective excitement). In the context of preserved libido and erectile function, ejaculation or orgasm may be specifically impaired by a variety of conditions such as neurological lesions of the sympathetic nervous system (e.g., retroperitoneal lymph node dissection, spinal cord injury), alpha blocker medications, or surgical disruption of the bladder neck with transurethral resection of the prostate or similar procedures. In these particular cases there may be preservation of orgasm. Conversely, it is possible for ejaculatory reflexes to be preserved, presuming an intact reflex arc to the SEG, in the context of psychological, cerebral, or other neurologic lesions that may impair the subjective experience of orgasm. The interplay between the “objective” (i.e., ejaculation) and “subjective” (i.e., orgasmic) elements of male sexual climax are complex and remain incompletely understood.
A variety of terms have been applied to the clinical phenomenon of ejaculation which occurs earlier than a man wishes during a sexual encounter. Ejaculatio Praecox is a historical term; more contemporary terminology includes PE, early ejaculation, rapid ejaculation, rapid climax, early orgasm, and premature climax. The Panel recognizes that all available terms have limitations; the Panel also recognizes that early experience of orgasm, not necessarily ejaculation, and the subsequent refractory period may be the most genuinely troublesome elements of this condition for most men. However, for the sake of familiarity, the most common term of PE is used throughout this document.
PE as a disorder has historically been difficult to define. In the 1960’s, Masters and Johnson defined PE as ejaculation that occurs before the female partner has experienced sexual climax during at least 50% of sexual encounters. This definition is problematic not only because it is specific to coitus but also because it does not take into considerations variations in female partner sexual response and context-specific factors that may lead to orgasmic delay in the female partner during coitus. Contemporary definitions have not focused on partner orgasmic response, although partner dissatisfaction or distress remain a consideration in making the diagnosis of PE.
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) defines PE as “a persistent or recurrent pattern of ejaculation occurring during partnered sexual activity within approximately 1 minute following vaginal penetration and before the individual wishes it.” The disorder must be present in 75% or more of sexual encounters and persistent over at least the last 6 months. To qualify as a dysfunction, the man must experience personal distress related to the dysfunction and the condition cannot be better explained by a comorbid or concomitant diagnosis. The DSM-V definition permits categorization of PE into lifelong versus acquired and generalized versus situational sub-types. Ejaculation that occurs before penetration or within 15 seconds, between 15-30 seconds after penetration, and from 30-60 seconds after penetration are categorized as severe, moderate, or mild PE, respectively. The empiric basis and clinical relevance of this distinction are not specified.
The World Health Organization’s International Classification of Diseases 11th edition (ICD-11) defines male early ejaculation as “ejaculation that occurs prior to or within a very short duration of the initiation of vaginal penetration or other relevant sexual stimulation, with no or little perceived control over ejaculation. The pattern of early ejaculation has occurred episodically or persistently over a period at least several months and is associated with clinically significant distress.” This definition has the advantage of being flexible and inclusive but lacks quantitative criteria and is nebulous in terms of the chronicity and frequency of disturbance required for the diagnosis. It mirrors the DSM-IV-TR diagnostic criterion that have been updated in DSM-V.
The International Society of Sexual Medicine (ISSM) defined two specific forms of PE (lifelong and acquired) with chronicity and time of onset as the principle distinguishing features. Per ISSM, PE is defined as ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE). Additional essential elements include the inability to delay ejaculation on all or nearly all vaginal penetrations and negative interpersonal consequences.7 This definition is to date the strongest in terms of evidence basis; this robust evidence basis is also a limitation in that the data used in its development were derived from studies of vaginal intercourse and hence it is explicitly specific to coitus.
Waldinger et al. conceptualized two provisional diagnoses that may be applicable in the context of men who have concerns about PE but do not meet specific criteria for either lifelong or acquired PE. Natural variable PE is defined as occasional short ELT that occurs irregularly and inconsistently and over which the man feels diminished sense of control. This condition is typically minimally or non-disruptive of overall sexual satisfaction and does not occur with a frequency that poses serious impediment for the patient. Subjective PE (SPE, also known as PE-like dysfunction) is defined as subjective concern or preoccupation about short ELT that is within population norms.24 Data on management of these provisional conditions is limited; for the time being education and/or psychosexual therapy, rather than pharmacotherapy, are favored as the treatments of choice for Natural variable PE and SPE
Similar to PE, the phenomenon of delay in ejaculation and/or orgasm has been difficult to define and is known by a variety of terms, including retarded ejaculation, inhibited ejaculation, and delayed orgasm. Recognizing again that ejaculation and orgasm are distinct entities and all available terms are limited, we will utilize the term DE throughout this text.
In 2010, the 3rd International Consultation on Sexual Dysfunction defined DE as the persistent or recurrent difficulty, delay in, or absence of attaining orgasm after sufficient sexual stimulation, which causes personal distress.
The DSM-V defines DE as the condition in which a man experiences “a marked delay in ejaculation” or “marked infrequency or absence of ejaculation.” The disorder must be present in 75% or more of partnered sexual encounters and persistent over at least the last 6 months. To qualify as a dysfunction, the patient must not desire delay of ejaculation and he must experience personal distress. Furthermore, the DE condition cannot be better explained by a comorbid or concomitant diagnosis or situation. The DSM-V definition permit categorization of DE into generalized versus situational sub-types and also includes an ordinal severity scale based on the degree of subjective distress (i.e., mild, moderate, and severe) rather than any quantitative measure. The DSM-V definition of "delay" does not have precise temporal boundaries, as there is no consensus as to what constitutes a reasonable time to reach orgasm or what is unacceptably long for most men and their sexual partners.
The ICD-11 defines “male delayed ejaculation” as “inability to achieve ejaculation or an excessive or increased latency of ejaculation, despite adequate sexual stimulation and the desire to ejaculate. The pattern of delayed ejaculation has occurred episodically or persistently over a period at least several months , and is associated with clinically significant distress.” Similar to the DSM-V definition for PE, this definition is limited by absence of quantitative criteria. The statement that the issue occurs “episodically or persistently” does not make clear the chronicity, frequency, or severity necessary to merit a DE diagnosis.
In 2015, the 4th International Consultation on Sexual Medicine developed new terminology for lifelong and acquired DE. Lifelong, alternatively classified as primary, delayed ejaculation was defined as a lifelong experience or inability to ejaculate in all of almost all (75%-100%) occasions of coital activity, associated with distress. Voluntary cessation of coital activity may subsequently occur after a variable time to avoid frustration, physical exhaustion, or genital irritation of self or partner. Men with lifelong DE might or might not be able to achieve ejaculation by subsequent non-coital activity, including masturbation.25
Acquired, alternatively classified as secondary, DE was defined in 2015 by the 4th International Consultation on Sexual Medicine as a distressing lengthening of ejaculatory latency that occurs in most (>50%) coital experiences after a period of normal ejaculatory function or a clinically meaningful change that results in distress. Voluntary cessation of coital activity may subsequently occur after a variable time to avoid frustration, physical exhaustion, or genital irritation of self or partner. Men with lifelong DE might or might not be able to achieve ejaculation by subsequent non-coital activity, including masturbation.25-28
The above criteria have been developed primarily from heterosexual samples engaging in penile-vaginal intercourse. There is no strong evidence to counter the assumption that these temporal and subjective criteria also apply to men with other sexual orientations or to other sexual situations and activities, e.g., MSM, anal intercourse, oral sex, and masturbation.
Other Ejaculatory Disorders
Hematospermia is defined as the presence of blood in ejaculated semen. It may present as bright red blood, clots, or disintegrating blood products. Although alarming, hematospermia is almost always benign; it may be found in association with other lower urinary tract conditions.29 Evaluation should proceed according to standard protocols based on associated symptoms and other risk factors (e.g., age, tobacco history, presence of hematuria, lower urinary tract symptoms [LUTS]).
Retrograde ejaculation is defined by ICD-11 as the condition in which semen is not ejected antegrade but rather flows into the bladder during climax. This is typically due to failure of the bladder neck to close during the emission phase and may be idiopathic or secondary to bladder neck surgery, pharmacological agents, or neurologic lesion. In most cases of retrograde ejaculation, orgasm occurs and feels pleasurable. Some men with retrograde ejaculation may report that their experience of orgasm is qualitatively different.
Anorgasmia may be conceptualized as an extreme variant of DE in which orgasm cannot be achieved. The ICD-11 defines anorgasmia as “the absence or marked infrequency of the orgasm experience or markedly diminished intensity of orgasmic sensations. The pattern of absence, delay, or diminished frequency or intensity of orgasm occurs despite adequate sexual stimulation, including the desire for sexual activity and orgasm, has occurred episodically or persistently over a period at least several months, and is associated with clinically significant distress.” The ICD-11 does not distinguish anorgasmia from DE and states that this would be diagnosed as male DE. For the purposes of this document anorgasmia is considered the condition in which sexual climax cannot be reached via any means of stimulation.
Anejaculation refers specifically to the absence of seminal ejaculation with sexual climax. Anejaculation may occur situationally or generally and may also occur with or without orgasmic sensation. Anejaculation most commonly occurs in the context of neurologic injury (e.g., spinal cord injury, neurodegenerative disease, retroperitoneal lymph node dissection).
Anhedonic orgasm is the condition in which ejaculation occurs but is not associated with subjective feelings of pleasure, intimacy, or relaxation. This condition is poorly understood but may relate to medications (particularly antidepressants), neurologic lesions, or psychogenic causes.30
Painful ejaculation, also known as dysejaculation, odynorgasmia, post orgasmic pain, dysorgasmia, or orgasmalgia, is a poorly understood condition that may have both psychogenic and organic elements. Pelvic lesion, traumas, or surgery may be contributing factors and painful ejaculation is often comorbid with other types of chronic pelvic pain syndromes.31 Men with painful ejaculation should be evaluated for lower urinary tract dysfunction and other causes of chronic pelvic pain.
Post Orgasmic Illness Syndrome (POIS)32-34 is provisional diagnosis which has been applied to cases of somatic symptoms that occur in close association with sexual climax. POIS is distinguished from painful ejaculation by the presence of symptoms outside the pelvis, such as malaise, confusion, myalgias, fatigue, or other somatic concerns. The etiology of POIS is unclear but may be an autoimmune, cytokine-mediated, or allergic reaction to seminal components has been proposed. The condition may be empirically managed with antihistamines, selective serotonin reuptake inhibitors (SSRIs), and benzodiazepines although data to support these modalities is scant.35
There is a wide range of ELT in men. Population data in non-clinical populations from Western countries suggest that the median ELT (measured by stop-watch timing) for men is between 5 and 6 minutes (standard deviation of about 7 minutes) after initiation of vaginal penetration. Latency time ranged between 6 seconds to 52 minutes; there was a slight but statistically significant decline in mean ELT with increasing age.36, 37 ELT of less than 2 minutes and less than 1 minute occurred in 2.5-6% and 0.5-3% of men, respectively. Time-based criteria have been incorporated as a component of most modern definitions of PE, derived in most cases from these population studies and driven by concerns that an absence of such could lead to a diagnosis of PE even in a man whose ELT is in the highest percentile group.
A number of international studies have demonstrated that up to 30% of men endorse early ejaculation.38-41 These findings have been used in numerous publications to support a claim that nearly one man in three has clinical PE. However, the majority of these studies included just a single item about early ejaculation without any quantification of chronicity or frequency nor assessment of personal or partner distress. Moreover, if men are asked whether they would like to last longer during sexual activity before they ejaculate, many will answer yes despite an absence of significant bother with their present time to ejaculation.
Although the prevalence of bothersome clinical PE is very unlikely to be 30%. PE is not rare and can be a source of considerable embarrassment and dissatisfaction. A synopsis of the most contemporary literature on early ejaculation occurring in the context of distress and absence of sense of control estimates that less than 5% of men have bothersome clinical PE.2
Similar data on the prevalence of DE are more limited; a substantial proportion of men in epidemiological studies report difficulty achieving orgasm, but the degree of associated distress is not reported. Amongst older men, DE is often co-morbid with issues of hypoactive sexual desire or ED and is therefore clinically silent; some patients may report “new onset” inability to achieve climax after institution of successful therapy for ED. Up to 25% of DE patients are reported to have lifelong issues with achieving orgasm during partnered sex.42 Interestingly, many men who report DE with a partner are able to achieve climax via masturbation.42 This situation may indicate a psychological or relational component.
Data on disorders of ejaculation outside of the context of coital intercourse are sparse. There is evidence to suggest that, in men with PE, the latency of ejaculation during masturbation tends to be longer than latency time for partnered sex. The difference in latency time between masturbation and coitus is less-pronounced in men not diagnosed with PE.43, 44 In a single survey study of Finnish men, the latency time between penetration and ejaculation was longer in men who climaxed via oral and anal sex compared to coital intercourse.45 There are no published stop-watch studies on ELT in MSM; despite the absence of stopwatch data on ELT, single item survey studies in MSM indicate that more than 30% endorse early ejaculation.46 Using more stringent criteria (e.g., validated scales, DSM-V criteria for the diagnosis) yields prevalence estimates for PE in MSM that are similar to those of strictly heterosexual men.47, 48
The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center (EPC). In conjunction with the Pacific Northwest EPC, the Disorders of Ejaculation Panel determined the guideline scope and reviewed the results of the systematic review to develop the recommendations and statements in this guideline.
The Disorders of Ejaculation Panel was created in 2018 by the American Urological Association Education and Research, Inc. (AUA). This guideline was developed in collaboration with the Sexual Medicine Society of North America (SMSNA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair who in turn appointed the additional panel members with expertise in urology and the psychology of sexual dysfunction. The Panel included patient representation. Funding of the Panel was provided by the AUA; panel members received no remuneration for their work.
Searches and Article Selection
A research librarian conducted searches in Ovid MEDLINE (1946 to March 1 2019), the Cochrane Central Register of Controlled Trials (through January 2019) and the Cochrane Database of Systematic Reviews (through March 1, 2019). Searches of electronic databases were supplemented by reviewing reference lists of relevant articles. An update search was conducted on September 5, 2019.
The methodology team developed criteria for inclusion and exclusion of studies based on the Key Questions and the populations, interventions, comparators, outcomes, timing, types of studies and settings of interest. For populations, inclusion focused on men older than 18 years engaging in penetrative intercourse who report distress and/or partner distress related to lifelong or acquired PE or DE, and those diagnosed with PE or DE and receiving treatment for these conditions. Interventions were behavioral therapies, pharmacological therapies, topical anesthetics (for PE) and various experimental therapies. Comparisons were against waitlist, no therapy, placebo, or another active intervention. Outcomes were intravaginal ejaculatory latency time (IELT), measured with a stopwatch or by self-report, ejaculatory control, patient or partner sexual satisfaction, quality of life, mood, composite measures of sexual function, and adverse events (AE). In addition to effectiveness and harms of interventions, Key Questions also addressed medical, psychological, situational, behavioral, and physical examination factors associated with PE or DE; the accuracy of scales or instruments for diagnosing PE; and the prevalence of laboratory abnormalities in persons with PE or DE.
For evaluation of interventions, the systematic review focused on randomized controlled trials (RCTs) and systematic reviews of RCTs. For evaluation of risk factors, scales or instruments, and laboratory abnormalities, the systematic review included studies on prevalence and diagnostic accuracy. Inclusion was restricted to articles published in peer-reviewed journals in or after 1994 (systematic reviews could include studies published prior to 1994). Studies on risk factors had to have sample sizes of at least 100 patients.
Using the pre-specified criteria, two investigators independently reviewed titles and abstracts of all citations. The methodology team used a two-phase method for screening full-text articles identified during review of titles and abstracts. In the first phase, investigators reviewed full-text articles to identify systematic reviews for inclusion. In the second phase they reviewed full-text articles to identify primary studies to address key questions and interventions not sufficiently answered by previously published systematic reviews, or studies published subsequent to the systematic reviews. Database searches resulted in 1,851 potentially relevant articles. After dual review of abstracts and titles, 223 systematic reviews and individual studies were selected for full-text dual review, and 8 systematic reviews and 59 individual studies were determined to meet inclusion criteria and were included in the review.
For primary studies that met inclusion criteria, information was abstracted on study design, year, setting (inpatient or outpatient), country, sample size, eligibility criteria, dose and duration of the intervention, population characteristics (i.e., age, race, type of ejaculatory disorder where applicable), results, and source of funding. For systematic reviews, characteristics were abstracted on the included studies (i.e., number, design, and sample sizes of included studies, study settings), population characteristics (i.e., inclusion and exclusion criteria), interventions, methods and ratings for the risk of bias of included studies, synthesis methods, and results. Data abstractions were reviewed by a second investigator for accuracy and discrepancies were resolved through discussion and consensus. All data abstractions were reviewed by a second investigator for accuracy. Discrepancies were resolved through discussion and consensus.
Risk of Bias Assessment
Two investigators independently assessed risk of bias using predefined criteria. Disagreements were resolved by consensus. For RCTs, criteria were adapted for assessing risk of bias from the U.S. Preventive Services Task Force. Criteria included use of appropriate randomization and allocation concealment methods, clear specification of inclusion criteria, baseline comparability of groups, blinding, attrition, and use of intention-to-treat analysis. Methodologists assessed systematic reviews using AMSTAR 2 (Assessing the Methodological Quality of Systematic Reviews) criteria. QUADAS-2 was used to assess the risk of bias of studies on diagnostic accuracy. Criteria included use of appropriate methods to select patients, avoidance of case-control design, use of an appropriate reference standard, blinding assessment of the index test and reference test, and administration of the reference standard in all patients. Studies were rated as “low risk of bias,” “medium risk of bias,” or “high risk of bias” based on the presence and seriousness of methodological shortcomings.
Studies rated “low risk of bias” are generally considered valid. “Low risk of bias” studies include clear descriptions of the population, setting, interventions, and comparison groups; a valid method for allocation of patients to treatment; low dropout rates and clear reporting of dropouts; blinding of patients, care providers, and outcome assessors; and appropriate analysis of outcomes.
Studies rated “medium risk of bias” are susceptible to some bias, though not necessarily enough to invalidate the results. These studies do not meet all the criteria for a rating of low risk of bias, but any flaw present is unlikely to cause major bias. Studies may be missing information, making it difficult to assess limitations and potential problems. The “medium risk of bias” category is broad, and studies with this rating vary in their strengths and weaknesses. Therefore, the results of some medium risk of bias studies are likely to be valid, while others are less likely to be valid.
Studies rated “high risk of bias” have significant flaws that may invalidate the results. They have a serious or “fatal” flaw in design, analysis, or reporting; large amounts of missing information; discrepancies in reporting; or serious problems in the delivery of the intervention. The results of high risk of bias studies could be as likely to reflect flaws in study design and conduct as true difference between compared interventions. Methodologists did not exclude studies rated high risk of bias a priori, but high risk of bias studies were considered to be less reliable than low or medium risk of bias studies. When possible, methodologists performed sensitivity analyses without high risk of bias studies to determine how their inclusion impacted findings. A complete list of the studies are available upon request at email@example.com.
Data Synthesis and Rating the Body of Evidence
The methodology team constructed evidence tables with study characteristics, results, and risk of bias ratings for all included studies, and summary tables to highlight the main findings, including pooled results from previously conducted meta-analyses in systematic reviews. Investigators did not update meta-analyses reported in systematic reviews with the results of new trials, but examined whether the findings of new trials were consistent with the reviews. There were too few trials of interventions not addressed in prior systematic reviews to conduct new (de novo) meta-analyses.
Determination of Evidence Strength
The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and is based on not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments. Investigators graded the strength of evidence for key comparisons and outcomes for each Key Question, using the approach described in the Agency for Healthcare Research and Quality Evidence-based Practice Center Methods Guide for Comparative Effectiveness and Effectiveness Reviews. Strength of evidence assessments were based on the following domains:
- Study limitations, based on the overall risk of bias across studies (low, medium, or high)
- Consistency of results across studies (consistent, inconsistent, or unable to determine when only one study was available)
- Directness of the evidence linking the intervention and health outcomes (direct or indirect)
- Precision of the estimate of effect, based on the number and size of studies and confidence intervals for the estimates (precise or imprecise)
- Reporting bias, based on whether the studies defined and reported primary outcomes and whether we identified relevant unpublished studies (suspected or undetected)
The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.
AUA Nomenclature: Linking Statement Type to Evidence Strength
The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk or burdens, and the Panel’s judgment regarding the balance between benefits and risks or burdens (Table 2). Strong Recommendations are directive statements that an action should (benefits outweigh risks or burdens) or should not (risks or burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks or burdens) or should not (risks or burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks or burdens is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks or burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risksor burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks orburdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.
Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged. A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.
|TABLE 1: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength|
|Evidence Strength A|
|Evidence Strength B|
|Evidence Strength C|
(Net benefit or harm substantial)
|Benefits > Risks/Burdens (or vice versa)|
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances and future research unlikely to change confidence
|Benefits > Risks/Burdens (or vice versa)|
Net benefit (or net harm) is substantial
Applies to most patients in most circumstances but better evidence could change confidence
|Benefits > Risks/Burdens (or vice versa)|
Net benefit (or net harm) appears substantial
Applies to most patients in most circumstances but better evidence is likely to change confidence
(rarely used to support a Strong Recommendation)
(Net benefit or harm moderate)
|Benefits > Risks/Burdens (or vice versa)|
Net benefit (or net harm) is moderate
Applies to most patients in most circumstances and future research is unlikely to change confidence
|Benefits > Risks/Burdens (or vice versa)|
Net benefit (or net harm) is moderate
Applies to most patients in most circumstances but better evidence could change confidence
|Benefits > Risks/Burdens (or vice versa)|
Net benefit (or net harm) appears moderate
Applies to most patients in most circumstances but better evidence is likely to change confidence
(No apparent net benefit or harm)
|Benefits = Risks/Burdens|
Best action depends on individual patient circumstances
Future research unlikely to change confidence
|Benefits = Risks/Burdens|
Best action appears to depend on individual patient circumstances
Better evidence could change confidence
|Balance between Benefits & Risks/Burdens unclear|
Alternative strategies may be equally reasonable
Better evidence likely to change confidence
|Clinical Principle||A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature|
|Expert Opinion||A statement, achieved by consensus of the Panel, that is based on members clinical training, experience, knowledge, and judgment for which there is no evidence|
Peer Review and Document Approval
An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and treatment of ejaculation disorders. In addition to reviewers from the AUA PGC, Science and Quality Council, and Board of Directors, the document was reviewed by representatives from SMSNA as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from December 9, 2019 to December 23, 2019 to allow additional interested parties to request a copy of the document for review. The guideline was sent to the Urology Care Foundation to open the document further to the patient perspective. The draft guideline document was distributed to 75 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 33 reviewers provided comments, including three external reviewers. At the end of the peer review process, a total of 433 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, Science and Quality Council, and Board of Directors, as well as the governing bodies of SMSNA for final approval.
Index Patient #1: Adult male who has experienced lifelong poor ejaculatory control, associated bother, and ejaculation within about 2 minutes of initiation of penetrative sex with a partner.
Index Patient #2: Adult male who has developed consistently poor ejaculatory control, associated bother, and ELT that is markedly reduced from prior sexual experience during penetrative sex with a partner.
These index patients are meant to represent common presentations of patients who have concerns about PE; index patient #1 is consistent with lifelong PE whereas index patient #2 is consistent with acquired PE. Individuals patients may vary in their particular concerns and preferences regarding treatment.
The criteria for the definitions of lifelong and acquired PE patients have been developed primarily from heterosexual samples engaging in penile-vaginal intercourse. There is no strong evidence to counter the assumption that these temporal and subjective criteria also apply to men with other sexual orientations and/or to other sexual situations or activities (e.g., MSM, anal sex, oral sex, masturbation).
Guideline Statement 1
Lifelong premature ejaculation is defined as poor ejaculatory control, associated bother, and ejaculation within about 2 minutes of initiation of penetrative sex that has been present since sexual debut. (Expert Opinion)
Guideline Statement 2
Acquired premature ejaculation is defined as consistently poor ejaculatory control, associated bother, and ejaculation latency that is markedly reduced from prior sexual experience during penetrative sex. (Expert Opinion)
Guideline Statement 3
Clinicians should assess medical, relationship, and sexual history and perform a focused physical exam to make the diagnosis of premature ejaculation. (Clinical Principle)
Guideline Statement 4
Clinicians may use validated instruments to assist in the diagnosis of PE. (Conditional Recommendation; Evidence Level: Grade C)
Guideline Statement 5
Clinicians should not use additional testing for the evaluation of a patient with lifelong premature ejaculation. (Conditional Recommendation; Evidence Level: Grade C)
Guideline Statement 6
Clinicians may utilize additional testing as clinically indicated for the evaluation of the patient with acquired premature ejaculation. (Conditional Recommendation; Evidence Level: Grade C)
Guideline Statement 7
Clinicians should advise patients that ejaculatory latency is not affected by circumcision status. (Conditional Recommendation; Evidence Level: Grade C)
Guideline Statement 8
Clinicians should consider referring men diagnosed with premature ejaculation to a mental health professional with expertise in sexual health. (Moderate Recommendation, Evidence Level: Grade C)
Numerous pharmacological treatments have been utilized for management of PE. These include SSRI, select tricyclic antidepressants (TCA), topical local anaesthetics, tramadol, phosphodiesterase type 5 inhibitors (PDE5i) and alpha-adrenergic blockers. The use of topical local anaesthetics, such as lidocaine, prilocaine or benzocaine, alone or in association, to diminish the sensitivity of the glans penis is the oldest known pharmacological treatment for PE.115 The utilization of specific SSRIs (i.e., paroxetine, sertraline, fluoxetine, and citalopram) and the TCA clomipramine has revolutionized the treatment of PE. These drugs block axonal re-uptake of serotonin from the synaptic cleft of central serotonergic neurons by 5-HT transporters, resulting in enhanced 5-HT neurotransmission and stimulation of post-synaptic membrane 5-HT receptors.
Men with Lifelong PE may be well managed with PE pharmacotherapy alone. Existing data are limited by tremendous heterogeneity in terms of outcome measures and treatment modalities. However, based on the Panel’s review of existing data, the majority of controlled studies suggest a clinically meaningful patient-reported response from treatment that exceeds placebo response rates by about 40-60%.112 Integration of patient and/or couple psychosexual therapy may enhance these effects. Men with acquired PE should receive etiology specific treatment if a specific cause can be identified (e.g., psychosexual counselling for men with recent trauma, appropriate pharmacotherapy for men with ED); this may be administered alone or in combination with PE-specific pharmacotherapy. Physicians should recognize the association between PE, comorbid ED, metabolic syndrome, sedentary lifestyle, alcohol consumption, and body mass index. Clinicians should counsel patients on the importance of exercise and other healthy lifestyle choices.116, 117
Guideline Statement 9
Clinicians should recommend daily SSRIs; on demand clomipramine or dapoxetine (where available); and topical penile anesthetics as first-line agents of choice in treatment of premature ejaculation. (Strong Recommendation; Evidence Level: Grade B)
Guideline Statement 10
Clinicians may consider on-demand dosing or tramadol for treatment of premature ejaculation in men who have failed first-line therapy pharmacotherapy. (Conditional Recommendation; Evidence Level: Grade C)
Guideline Statement 11
Clinicians may consider treating men with premature ejaculation who have failed first-line therapy with α1-adrenoreceptor antagonists (Expert Opinion)
Guideline Statement 12
Clinicians should treat comorbid erectile dysfunction in patients with premature ejaculation according to the AUA Guidelines on Erectile Dysfunction. (Expert Opinion)
Guideline Statement 13
Clinicians should advise men with premature ejaculation that combining behavioral and pharmacological approaches may be more effective than either modality alone. (Moderate Recommendation; Evidence Level: Grade B)
Guideline Statement 14
Clinicians should advise patients that there is insufficient evidence to support the use of alternative therapies in the treatment of premature ejaculation. (Expert Opinion)
Guideline Statement 15
Clinicians should inform patients that surgical management (including injection of bulking agents) of premature ejaculation should be considered experimental and only be used in the context of an ethical board approved clinical trial. (Expert Opinion)
Index Patient #3: Adult male patient who has consistent and bothersome difficulty achieving orgasm during penetrative sex with a partner.
Guideline Statement 16
Lifelong delayed ejaculation is defined as lifelong, consistent, bothersome inability to achieve ejaculation, or excessive latency of ejaculation, despite adequate sexual stimulation and the desire to ejaculate. (Expert Opinion)
Guideline Statement 17
Acquired delayed ejaculation is defined as an acquired, consistent, bothersome inability to achieve ejaculation, or an increased latency of ejaculation, despite adequate sexual stimulation and the desire to ejaculate. (Expert Opinion)
Guideline Statement 18
Clinicians should assess medical, relationship, and sexual history and perform a focused physical exam to evaluate a patient with delayed ejaculation. (Clinical Principle)
Guideline Statement 19
Clinicians may utilize additional testing as clinically indicated for the evaluation of delayed ejaculation. (Conditional Recommendation; Evidence Level: Grade C)
Guideline Statement 20
Clinicians should consider referring men diagnosed with lifelong or acquired delayed ejaculation to a mental health professional with expertise in sexual health. (Expert Opinion)
Guideline Statement 21
Clinicians should advise men with delayed ejaculation that modifying sexual positions or practices to increase arousal may be of benefit. (Expert Opinion)
Guideline Statement 22
Clinicians should suggest replacement, dose adjustment, or staged cessation or of medications that may contribute to delayed ejaculation (Clinical Principle)
Guideline Statement 23
Clinicians should inform patients that there is insufficient evidence to assess the risk-benefit ratio of oral pharmacotherapy for the management of delayed ejaculation. (Expert Opinion)
Guideline Statement 24
Clinicians may offer treatment to normalize serum testosterone levels in patients with delayed ejaculation and testosterone deficiency. (Expert Opinion)
Guideline Statement 25
Clinicians should treat men who have delayed ejaculation and comorbid erectile dysfunction according to the AUA Guidelines on Erectile Dysfunction. (Expert Opinion)
Guideline Statement 26
Clinicians should counsel patients with delayed ejaculation that no currently available data indicates that invasive non-pharmacological strategies are of benefit. (Expert Opinion)
Work continues on better means to elucidate the etiology for PE. Assessment of vibrational thresholds, nerve conduction times, somatosensory latency testing, and others are currently useful for research purposes but may in the future have clinical relevance. Improvements in our understanding of the relationship between androgens and ejaculation and orgasm may also permit more nuanced guidance on androgen therapy for ejaculation concerns. Novel molecules, including melatonin, carbon monoxide, and nitric oxide may also have relevance to ejaculation and orgasm that is not completely understood.
Botulinum toxin is a protein and neurotoxin produced by the bacterium Clostridium Botulinum. It is a selective blocker of acetylcholine release from nerve endings which blocks neural transmission when injected into muscle.218 This drug has been widely used as a cosmetic anti-ageing treatment, and as a medical treatment for a diverse range of conditions including neurogenic detrusor overactivity.264
Serefoglu and Silay theorized that the repeated contractions of bulbospongiosus and ischiocavernosus muscles during the ejection phase of ejaculation may be inhibited by the injection of botulinum-A toxin.219 They subsequently demonstrated that percutaneous injection of botulinum-A toxin into the bulbospongiosus muscle bilaterally increased ejaculatory latency in male rats in a dose-dependent manner compared to pre-treatment latency.220 However, the difference between the post-treatment geometric mean ejaculatory latency of botulinum-A toxin and saline failed to reach statistical significance possibly due to the small sample size and/or the high variability in ELT.
Botulinum-A toxin may be a safe and effective means to prolong ejaculatory latency without affecting other aspects of sexual behaviour. However, dose-ranging Phase II clinical trials of botulinum-A toxin as a treatment for PE in humans were discontinued due to lack of efficacy in interim analysis. Until data become available botulinum-A toxin should not be considered as standard of care in PE.
Modafinil is a wake-promoting agent used for the treatment of narcolepsy with a complex and poorly understood mechanism of action upon dopamine, serotonin, g-Aminobutyric acid (GABA)/glutamate and orexin-containing neurons.265,266 Several pre-clinical studies support modafinil as a potential treatment for PE.267-271 An uncontrolled pilot study of on-demand modafinil in treatment-naïve men with lifelong PE reported a modest but significant two-fold change in self-reported IELT and positive PROs.221 The short-acting modafinil d-isomer is undergoing pre-clinical trials as an investigational drug for the “on demand” treatment of PE.
Oxytocin is a peptide hormone of nine amino acids which facilitates sexual reproduction in mammals.222 An increasing number of studies report the involvement of central and peripheral oxytocinergic neurotransmission in the ejaculatory process.223-225 In human males, plasma oxytocin levels are elevated during penile erection and at the time of orgasm.272,273 Systematic administration of oxytocin decreases the number of intromissions required for ejaculation in young adult rats,274 and reduces ejaculation latencies and post-ejaculation intervals in older sexually sluggish rats.275,276 Several pre-clinical studies suggest a potential role for highly selective oxytocin receptor antagonists in the treatment of PE.277-279
In a placebo controlled RCT of epelsiban in men with PE, Shinghai et al., demonstrated that 50 mg and 150 mg were well tolerated but did not result in a clinically nor statistically significant change in ELT in men with PE, compared with placebo.280 The failure of this study to demonstrate efficacy is likely due to the inability of epelsiban to penetrate the blood brain barrier and enter the CNS. The molecular weight of epelsiban is 518.6 Da and exceeds the 400 Da threshold for blood brain lipid membrane permeation.281
Cligosoban is a small molecule oxytocin receptor antagonist (MW 419.65 Da) with adequate CNS penetration in pre-clinical studies.282 A phase IIA double-blind placebo controlled RCT trial in men with lifelong PE demonstrated clinically and statistically significant treatment-related effects for geometric ELT (3.6 fold versus 1.8 for placebo) and the PROs of ejaculation control and ejaculation-related distress.283 Although a post-hoc exploratory analyses demonstrated a direct dose-response relationship and suggested a potential for increased efficacy when larger doses are administered, a second fixed dose study using higher doses failed to demonstrate statistically significant treatment outcomes.284
Oxytocin antagonists are an appealing target for PE therapy given their mode of action and relevance to ejaculation reflexes. Further study and potentially development of agents with different distribution is required to determine if these therapies will have a role in PE management in the future.
With regards to DE, there is a pressing need for additional epidemiological data and development of evidence-based definitions. Novel imaging modalities may play a role in providing clinically usable data in the future.237 Appropriately designed studies to establish the prevalence and characteristics of DE will enable better designed clinical trials which will provide a more robust evidence basis for management.
- Serefoglu EC, McMahon CG, Waldinger MD et al: An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. Journal of Sexual Medicine 2014; 11: 1423.
- Althof SE, McMahon CG, Waldinger MD et al: An Update of the International Society of Sexual Medicine's Guidelines for the Diagnosis and Treatment of Premature Ejaculation (PE). Sex Med 2014; 2: 60.
- Holmes G, Galitz L, Hu P et al: Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol 2005; 60: 469.
- Giuliano F and Clement P: Physiology of ejaculation: emphasis on serotonergic control. Eur Urol 2005; 48: 408.
- Clement P and Giuliano F: Physiology and Pharmacology of Ejaculation. Basic Clin Pharmacol Toxicol 2016; 119 Suppl 3: 18.
- Althof SE and McMahon CG: Contemporary Management of Disorders of Male Orgasm and Ejaculation. Urology 2016; 93: 9.
- Serefoglu EC, McMahon CG, Waldinger MD et al: An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second international society for sexual medicine ad hoc committee for the definition of premature ejaculation. Sex Med 2014; 2: 41.
- Althof SE: Psychosexual therapy for premature ejaculation. Transl Androl Urol 2016; 5: 475.
- Perelman MA: The sexual tipping point: a mind/body model for sexual medicine. J Sex Med 2009; 6: 629.
- Chehensse C, Facchinetti P, Bahrami S et al: Human spinal ejaculation generator. Ann Neurol 2017; 81: 35.
- Roehrborn CG, Manyak MJ, Palacios-Moreno JM et al: A prospective randomised placebo-controlled study of the impact of dutasteride/tamsulosin combination therapy on sexual function domains in sexually active men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). BJU Int 2018; 121: 647.
- Sun F, Sun X, Shi Q et al: Transurethral procedures in the treatment of benign prostatic hyperplasia: A systematic review and meta-analysis of effectiveness and complications. Medicine (Baltimore) 2018; 97: e13360.
- Pham H and Sharma P: Emerging, newly-approved treatments for lower urinary tract symptoms secondary to benign prostatic hypertrophy. Can J Urol 2018; 25: 9228.
- Sullivan JF, Stember DS, Deveci S et al: Ejaculation profiles of men following radiation therapy for prostate cancer. J Sex Med 2013; 10: 1410.
- Shindel AW: Anejaculation: Relevance to Sexual Enjoyment in Men and Women. J Sex Med 2019; 16: 1324.
- Bridges AJ, Wosnitzer R, Scharrer E et al: Aggression and sexual behavior in best-selling pornography videos: a content analysis update. Violence Against Women 2010; 16: 1065.
- Prestage G, Hurley M and Brown G: "Cum play" among gay men. Arch Sex Behav 2013; 42: 1347.
- Burri A, Buchmeier J and Porst H: The Importance of Male Ejaculation for Female Sexual Satisfaction and Function. J Sex Med 2018; 15: 1600.
- Seizert CA: The neurobiology of the male sexual refractory period. Neurosci Biobehav Rev 2018; 92: 350.
- De Lorme KC and Sisk CL: The organizational effects of pubertal testosterone on sexual proficiency in adult male Syrian hamsters. Physiol Behav 2016; 165: 273.
- Schulz KM and Sisk CL: Pubertal hormones, the adolescent brain, and the maturation of social behaviors: Lessons from the Syrian hamster. Mol Cell Endocrinol 2006; 254-255: 120.
- De Lorme KC, Staffend-Michael NA, Simmons SC et al: Pubertal Testosterone Programs Adult Behavioral Adaptations to Sexual Experience through Infralimbic Cortex DeltaFosB. eNeuro 2019; 6.
- Khan HL, Bhatti S, Abbas S et al: Serotonin transporter (5-HTTLPR) genotypes and trinucleotide repeats of androgen receptor exert a combinatorial effect on hormonal milieu in patients with lifelong premature ejaculation. Andrology 2018; 6: 916.
- Waldinger MD: Premature ejaculation: different pathophysiologies and etiologies determine its treatment. J Sex Marital Ther 2008; 34: 1.
- McCabe MP, Sharlip ID, Atalla E et al: Definitions of Sexual Dysfunctions in Women and Men: A Consensus Statement From the Fourth International Consultation on Sexual Medicine 2015. J Sex Med 2016; 13: 135.
- Cronbach LJ and Meehl PE: Construct validity in psychological tests. Psychol Bull 1955; 52: 281.
- Rowland D, McMahon CG, Abdo C et al: Disorders of orgasm and ejaculation in men. J Sex Med 2010; 7: 1668.
- Patrick DL, Althof SE, Pryor JL et al: Premature ejaculation: an observational study of men and their partners. J Sex Med 2005; 2: 358.
- Suh Y, Gandhi J, Joshi G et al: Etiologic classification, evaluation, and management of hematospermia. Transl Androl Urol 2017; 6: 959.
- Rosenbaum JF and Pollack MH: Anhedonic ejaculation with desipramine. Int J Psychiatry Med 1988; 18: 85.
- Parnham A and Serefoglu EC: Classification and definition of premature ejaculation. Translational Andrology and Urology 2016; 5: 416.
- Waldinger MD: Post orgasmic illness syndrome (POIS). Transl Androl Urol 2016; 5: 602.
- Waldinger MD, Meinardi MM, Zwinderman AH et al: Postorgasmic Illness Syndrome (POIS) in 45 Dutch caucasian males: clinical characteristics and evidence for an immunogenic pathogenesis (Part 1). J Sex Med 2011; 8: 1164.
- Jiang N, Xi G, Li H et al: Postorgasmic illness syndrome (POIS) in a Chinese man: no proof for IgE-mediated allergy to semen. J Sex Med 2015; 12: 840.
- Nguyen HMT, Bala A, Gabrielson AT et al: Post-Orgasmic Illness Syndrome: A Review. Sex Med Rev 2018; 6: 11.
- Waldinger MD, Quinn P, Dilleen M et al: A multinational population survey of intravaginal ejaculation latency time. J Sex Med 2005; 2: 492.
- Waldinger MD, McIntosh J and Schweitzer DH: A five-nation survey to assess the distribution of the intravaginal ejaculatory latency time among the general male population. J Sex Med 2009; 6: 2888.
- Laumann EO, Paik A and Rosen RC: Sexual dysfunction in the United States: prevalence and predictors. Jama 1999; 281: 537.
- Nicolosi A, Laumann EO, Glasser DB et al: Sexual activity, sexual disorders and associated help-seeking behavior among mature adults in five Anglophone countries from the Global Survey of Sexual Attitudes and Behaviors (GSSAB). J Sex Marital Ther 2006; 32: 331.
- Nicolosi A, Buvat J, Glasser DB et al: Sexual behaviour, sexual dysfunctions and related help seeking patterns in middle-aged and elderly Europeans: the global study of sexual attitudes and behaviors. World J Urol 2006; 24: 423.
- Lindau ST, Schumm LP, Laumann EO et al: A study of sexuality and health among older adults in the United States. N Engl J Med 2007; 357: 762.
- Perelman MA and Rowland DL: Retarded ejaculation. World J Urol 2006; 24: 645.
- Rowland DL, Strassberg DS, de Gouveia Brazao CA et al: Ejaculatory latency and control in men with premature ejaculation: an analysis across sexual activities using multiple sources of information. J Psychosom Res 2000; 48: 69.
- Strassberg DS, Kelly MP, Carroll C et al: The psychophysiological nature of premature ejaculation. Arch Sex Behav 1987; 16: 327.
- Jern P, Santtila P, Johansson A et al: Subjectively measured ejaculation latency time and its association with different sexual activities while controlling for age and relationship length. J Sex Med 2009; Jern P, Santtila P, Johansson A et al: Subjectively measured ejaculation latency time and its association with different sexual activities while controlling for age and relationship length. J Sex Med 2009; 6: 2568.: 2568.
- Hirshfield S, Chiasson MA, Wagmiller RL, Jr. et al: Sexual dysfunction in an Internet sample of U.S. men who have sex with men. J Sex Med 2010; 7: 3104.
- Breyer BN, Smith JF, Eisenberg ML et al: The impact of sexual orientation on sexuality and sexual practices in North American medical students. J Sex Med 2010; 7: 2391.
- Son H, Song SH, Kim SW et al: Self-reported premature ejaculation prevalence and characteristics in Korean young males: community-based data from an internet survey. J Androl 2010; 31: 540.
- Ventus D, Ristila M, Gunst A et al: A Longitudinal Analysis of Premature Ejaculation Symptoms Raises Concern Regarding the Appropriateness of a "Lifelong" Subtype. Eur Urol Focus 2017; 3: 243.
- Patrick DL, Rowland D and Rothman M: Interrelationships among measures of premature ejaculation: the central role of perceived control. J Sex Med 2007; 4: 780.
- Bandura A: Regulation of cognitive processes through perceived self-efficacy. Developmental Psychology 1989; 25: 729.
- Shabsigh R, Patrick DL, Rowland DL et al: Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine. BJU Int 2008; 102: 824.
- Giuliano F, Patrick DL, Porst H et al: Premature ejaculation: results from a five-country European observational study. Eur Urol 2008; 53: 1048.
- Strauss ME and Smith GT: Construct validity: advances in theory and methodology. Annu Rev Clin Psychol 2009; 5: 1.
- Rowland DL and Kolba TN: Understanding the effects of establishing various cutoff criteria in the definition of men with premature ejaculation. J Sex Med 2015; 12: 1175.
- McMahon CG, Althof SE, Kaufman JM et al: Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials. J Sex Med 2011; 8: 524.
- Porst H, McMahon CG, Althof SE et al: Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials. J Sex Med 2010; 7: 2231.
- McMahon CG, Jannini E, Waldinger M et al: Standard operating procedures in the disorders of orgasm and ejaculation. J Sex Med 2013; 10: 204.
- Gao J, Zhang X, Su P et al: Prevalence and factors associated with the complaint of premature ejaculation and the four premature ejaculation syndromes: a large observational study in China. J Sex Med 2013; 10: 1874.
- Porst H, Montorsi F, Rosen RC et al: The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol 2007; 51: 816.
- Rowland D, Perelman M, Althof S et al: Self-reported premature ejaculation and aspects of sexual functioning and satisfaction. J Sex Med 2004; 1: 225.
- Symonds T, Roblin D, Hart K et al: How does premature ejaculation impact a man s life? J Sex Marital Ther 2003; 29: 361.
- Xia Y, Li J, Shan G et al: Relationship between premature ejaculation and depression: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2016; 95: e4620.
- Rosen RC, McMahon CG, Niederberger C et al: Correlates to the clinical diagnosis of premature ejaculation: results from a large observational study of men and their partners. Journal of Urology 2007; 177: 1059.
- Jern P, Piha J and Santtila P: Validation of three early ejaculation diagnostic tools: a composite measure is accurate and more adequate for diagnosis by updated diagnostic criteria. PLoS ONE [Electronic Resource] 2013; 8: e77676.
- Pakpour AH, Yekaninejad MS, Nikoobakht MR et al: Psychometric properties of the iranian version of the premature ejaculation diagnostic tool. Sexual Medicine 2014; 2: 31.
- Serefoglu EC, Yaman O, Cayan S et al: The comparison of premature ejaculation assessment questionnaires and their sensitivity for the four premature ejaculation syndromes: results from the Turkish society of andrology sexual health survey. Journal of Sexual Medicine 2011; 8: 1177.
- Song SH, Choi WS, Son H et al: Validity of the premature ejaculation diagnostic tool in four subgroups of premature ejaculation syndrome: Data from the korean internet sexuality survey-Part 1. Sexual Health 2014; 11: 73.
- Althof S, Rosen R, Symonds T et al: Development and validation of a new questionnaire to assess sexual satisfaction, control, and distress associated with premature ejaculation. J Sex Med 2006; 3: 465.
- Corona G, Jannini EA, Vignozzi L et al: The hormonal control of ejaculation. Nat Rev Urol 2012; 9: 508.
- Culha MG, Tuken M, Gonultas S et al: Frequency of etiological factors among patients with acquired premature ejaculation: prospective, observational, single-center study. Int J Impot Res 2020; 32: 352.
- Corona G, Jannini EA, Mannucci E et al: Different testosterone levels are associated with ejaculatory dysfunction. J Sex Med 2008; 5: 1991.
- El-Sakka AI: Premature ejaculation in non-insulin-dependent diabetic patients. Int J Androl 2003; 26: 329.
- Waldinger MD, Zwinderman AH, Olivier B et al: Thyroid-stimulating hormone assessments in a Dutch cohort of 620 men with lifelong premature ejaculation without erectile dysfunction. Journal of Sexual Medicine 2005; 2: 865.
- Canat L, Erbin A, Canat M et al: Assessment of hormonal activity in patients with premature ejaculation. International Braz J Urol 2017; 43: 311.
- Peng DW, Gao JJ, Huang YY et al: Association between polymorphisms in the human serotonin transporter gene and lifelong premature ejaculation in the Han population. Asian J Androl 2018; 20: 103.
- Jern P and Ventus D: Serotonergic polymorphisms in the control of ejaculation. Mol Cell Endocrinol 2018; 467: 60.
- Janssen PK, van Schaik R, Zwinderman AH et al: The 5-HT(1)A receptor C(1019)G polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. Pharmacol Biochem Behav 2014; 121: 184.
- Santtila P, Jern P, Westberg L et al: The dopamine transporter gene (DAT1) polymorphism is associated with premature ejaculation. Journal of Sexual Medicine 2010; 7: 1538.
- Roaiah MF, Elkhayat YI, Rashed LA et al: Study of the prevalence of 5 HT-2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation. Andrologia 2018; 50.
- Zhu L, Mi Y, You X et al: A meta-analysis of the effects of the 5-hydroxytryptamine transporter gene-linked promoter region polymorphism on susceptibility to lifelong premature ejaculation. PLoS One 2013; 8: e54994.
- Janssen PK, Schaik R, Olivier B et al: The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. Asian Journal of Andrology 2014; 16: 607.
- Eltonsi TK, Tawfik TM, Rashed LA et al: Study of the link between dopamine transporter gene polymorphisms and response to paroxetin and escitalopram in patients with lifelong premature ejaculation. Int J Impot Res 2017; 29: 235.
- Salem AM, Kamel, II, Rashed LA et al: Effects of paroxetine on intravaginal ejaculatory latency time in Egyptian patients with lifelong premature ejaculation as a function of serotonin transporter polymorphism. Int J Impot Res 2017; 29: 7.
- Xin ZC, Chung WS, Choi YD et al: Penile sensitivity in patients with primary premature ejaculation. J Urol 1996; 156: 979.
- Wiggins A, Farrell MR, Tsambarlis P et al: The Penile Sensitivity Ratio: A Novel Application of Biothesiometry to Assess Changes in Penile Sensitivity. J Sex Med 2019; 16: 447.
- Atalay HA, Sonkaya AR, Ozbir S et al: Are There Differences in Brain Morphology in Patients with Lifelong Premature Ejaculation? J Sex Med 2019; 16: 992.
- Gao M, Yang X, Liu L et al: Abnormal White Matter Microstructure in Lifelong Premature Ejaculation Patients Identified by Tract-Based Spatial Statistical Analysis. J Sex Med 2018; 15: 1272.
- Lu J, Zhang X, Wang H et al: Short- and long-range synergism disorders in lifelong premature ejaculation evaluated using the functional connectivity density and network property. Neuroimage Clin 2018; 19: 607.
- Yang X, Gao M, Zhang L et al: Central Neural Correlates During Inhibitory Control in Lifelong Premature Ejaculation Patients. Front Hum Neurosci 2018; 12: 206.
- Serefoglu EC, Yaman O, Cayan S et al: Prevalence of the complaint of ejaculating prematurely and the four premature ejaculation syndromes: results from the Turkish Society of Andrology Sexual Health Survey. J Sex Med 2011; 8: 540.
- Zhang X, Gao J, Liu J et al: Distribution and factors associated with four premature ejaculation syndromes in outpatients complaining of ejaculating prematurely. J Sex Med 2013; 10: 1603.
- Burnett AL, Nehra A, Breau RH et al: Erectile Dysfunction: AUA Guideline. J Urol 2018; 200: 633.
- Basile Fasolo C, Mirone V, Gentile V et al: Premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001--a study of the Italian Society of Andrology (SIA). Journal of Sexual Medicine 2005; 2: 376.
- Majzoub A, Arafa M, Al-Said S et al: Premature ejaculation in type II diabetes mellitus patients: Association with glycemic control. Translational Andrology and Urology 2016; 5: 248.
- Bellastella G, Maiorino MI, Olita L et al: Premature ejaculation is associated with glycemic control in Type 1 diabetes. Journal of Sexual Medicine 2015; 12: 93.
- Donatucci CF: Etiology of ejaculation and pathophysiology of premature ejaculation. J Sex Med 2006; 3 Suppl 4: 303.
- Zohdy W: Clinical parameters that predict successful outcome in men with premature ejaculation and inflammatory prostatitis. J Sex Med 2009; 6: 3139.
- Shamloul R and el-Nashaar A: Chronic prostatitis in premature ejaculation: a cohort study in 153 men. J Sex Med 2006; 3: 150.
- Sharlip ID: Guidelines for the diagnosis and management of premature ejaculation. J Sex Med 2006; 3 Suppl 4: 309.
- El-Nashaar A and Shamloul R: Antibiotic treatment can delay ejaculation in patients with premature ejaculation and chronic bacterial prostatitis. J Sex Med 2007; 4: 491.
- Screponi E, Carosa E, Di Stasi SM et al: Prevalence of chronic prostatitis in men with premature ejaculation. Urology 2001; 58: 198.
- Yang Y, Wang X, Bai Y et al: Circumcision does not have effect on premature ejaculation: A systematic review and meta-analysis. Andrologia 2018; 50.
- Rowland DL, Patrick DL, Rothman M et al: The psychological burden of premature ejaculation. J Urol 2007; 177: 1065.
- Rosen RC and Althof S: Impact of premature ejaculation: the psychological, quality of life, and sexual relationship consequences. J Sex Med 2008; 5: 1296.
- Canat L, Degirmentepe RB, Atalay HA et al: The relationship between female sexual function index domains and premature ejaculation. Int Urol Nephrol 2018; 50: 633.
- Limoncin E, Tomassetti M, Gravina GL et al: Premature ejaculation results in female sexual distress: standardization and validation of a new diagnostic tool for sexual distress. J Urol 2013; 189: 1830.
- Burri A, Giuliano F, McMahon C et al: Female partner's perception of premature ejaculation and its impact on relationship breakups, relationship quality, and sexual satisfaction. J Sex Med 2014; 11: 2243.
- Shindel AW, Nelson CJ, Naughton CK et al: Premature ejaculation in infertile couples: prevalence and correlates. J Sex Med 2008; 5: 485.
- Albaugh JA and Kellogg-Spadt S: Sensate focus and its role in treating sexual dysfunction. Urol Nurs 2002; 22: 402.
- de Carufel F and Trudel G: Effects of a new functional-sexological treatment for premature ejaculation. J Sex Marital Ther 2006; 32: 97.
- Cooper K, Martyn-St James M, Kaltenthaler E et al: Behavioral Therapies for Management of Premature Ejaculation: A Systematic Review. Sex Med 2015; 3: 174.
- Cormio L, Massenio P, La Rocca R et al: The Combination of Dapoxetine and Behavioral Treatment Provides Better Results than Dapoxetine Alone in the Management of Patients with Lifelong Premature Ejaculation. Journal of Sexual Medicine 2015; 12: 1609.
- Jern P: Evaluation of a behavioral treatment intervention for premature ejaculation using a handheld stimulating device. J Sex Marital Ther 2014; 40: 358.
- van Lankveld JJ, Leusink P, van Diest S et al: Internet-based brief sex therapy for heterosexual men with sexual dysfunctions: a randomized controlled pilot trial. J Sex Med 2009; 6: 2224.
- Schapiro B: Premature ejaculation, a review of 1130 cases. Journal of Urology 1943; 50: 374.
- Ventus D and Jern P: Lifestyle Factors and Premature Ejaculation: Are Physical Exercise, Alcohol Consumption, and Body Mass Index Associated With Premature Ejaculation and Comorbid Erectile Problems? Journal of Sexual Medicine 2016; 13: 1482.
- Kilinc MF, Aydogmus Y, Yildiz Y et al: Impact of physical activity on patient self-reported outcomes of lifelong premature ejaculation patients: Results of a prospective, randomised, sham-controlled trial. Andrologia 2017.
- Waldinger M, Zwinderman A, Schweitzer D et al: Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: A systematic review and metaanalysis. International Journal of Impotence Research 2004: 1.
- McMahon CG and Touma K: Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. J Urol 1999; 161: 1826.
- Strassberg DS, de Gouveia Brazao CA, Rowland DL et al: Clomipramine in the treatment of rapid (premature) ejaculation. J Sex Marital Ther 1999; 25: 89.
- Kim SW and 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.
- Waldinger MD, Zwinderman AH and 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.
- Choi JB, Kang SH, Lee DH et al: Efficacy and Safety of On Demand Clomipramine for the Treatment of Premature Ejaculation: A Multicenter, Randomized, Double-Blind, Phase III Clinical Trial. Journal of Urology 2019; 201: 147.
- McMahon CG: Long term results of treatment of premature ejaculation with selective serotonin re-uptake inhibitors. IntJImpRes 2002; 14: S19.
- Sun Y, Yang L, Bao Y et al: Efficacy of PDE5Is and SSRIs in men with premature ejaculation: a new systematic review and five meta-analyses. World J Urol 2017; 35: 1817.
- Waldinger MD: Premature ejaculation: definition and drug treatment. Drugs 2007; 67: 547.
- Ables AZ and Nagubilli R: Prevention, recognition, and management of serotonin syndrome. Am Fam Physician 2010; 81: 1139.
- Wang RZ, Vashistha V, Kaur S et al: Serotonin syndrome: Preventing, recognizing, and treating it. Cleve Clin J Med 2016; 83: 810.
- Boyer EW and Shannon M: The Serotonin Syndrome. New England Journal of Medicine 2005; 352: 1112.
- Marangell L, Dennehy E, Wisniewski S et al: Case-control analyses of the impact of pharmacotherapy on prospectively observed suicide attempts and completed suicides in bipolar disorder: findings from STEP-BD Journal of Clinical Psychiatry 2008; 69: 916.
- Verze P, Cai T, Magno C et al: Comparison of Treatment Emergent Adverse Events in Men With Premature Ejaculation Treated With Dapoxetine and Alternate Oral Treatments: Results From a Large Multinational Observational Trial. Journal of Sexual Medicine 2016; 13: 194.
- Li N, Wallen NH, Ladjevardi M et al: Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinolysis 1997; 8: 517.
- Fava M, Judge R, Hoog SL et al: Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry 2000; 61: 863.
- Akasheh G, Sirati L, Noshad Kamran AR et al: Comparison of the effect of sertraline with behavioral therapy on semen parameters in men with primary premature ejaculation. Urology 2014; 83: 800.
- Koyuncu H, Serefoglu EC, Ozdemir AT et al: Deleterious effects of selective serotonin reuptake inhibitor treatment on semen parameters in patients with lifelong premature ejaculation. Int J Impot Res 2012; 24: 171.
- Sharma T, Guski LS, Freund N et al: Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. Bmj 2016; 352: i65.
- Khan A, Khan S, Kolts R et al: Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. American Journal of Psychiatry 2003; 160: 790.
- Salonia A, Rocchini L, Sacca A et al: Acceptance of and discontinuation rate from paroxetine treatment in patients with lifelong premature ejaculation. Journal of Sexual Medicine 2009; 6: 2868.
- Black K, Shea CA, Dursun S et al: Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. Journal of Psychiatry and Neuroscience 2000; 25: 255.
- Pryor JL, Althof SE, Steidle C et al: Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet 2006; 368: 929.
- Yue FG, Dong L, Hu TT et al: Efficacy of Dapoxetine for the treatment of premature ejaculation: a meta-analysis of randomized clinical trials on intravaginal ejaculatory latency time, patient-reported outcomes, and adverse events. Urology 2015; 85: 856.
- McMahon CG, Giuliano F, Dean J et al: Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study. J Sex Med 2013; 10: 2312.
- Tuken M, Culha MG and Serefoglu EC: Efficacy and safety of dapoxetine/sildenafil combination tablets in the treatment of men with premature ejaculation and concomitant erectile dysfunction-DAP-SPEED Study. Int J Impot Res 2019; 31: 92.
- Li J, Yuan H, Bai Y et al: Dapoxetine for premature ejaculation: an updated meta-analysis of randomized controlled trials. Clin Ther 2014; 36: 2003.
- Levine L: Evaluation of Withdrawal Effects with Dapoxetine in the Treatment of Premature Ejaculation (PE). In: Poster presented at SMSNA 2006
- Jiann BP and Huang YJ: Assessing satisfaction in men with premature ejaculation after dapoxetine treatment in real-world practice. Int J Clin Pract 2015; 69: 1326.
- Park HJ, Park NC, Kim TN et al: Discontinuation of Dapoxetine Treatment in Patients With Premature Ejaculation: A 2-Year Prospective Observational Study. Sex Med 2017; 5: e99.
- Mondaini N, Fusco F, Cai T et al: Dapoxetine treatment in patients with lifelong premature ejaculation: the reasons of a "Waterloo". Urology 2013; 82: 620.
- Butcher MJ, Zubert T, Christiansen K et al: Topical Agents for Premature Ejaculation: A Review. Sex Med Rev 2019.
- Martyn-St James M, Cooper K, Ren K et al: Topical anaesthetics for premature ejaculation: a systematic review and meta-analysis. Sexual Health 2016; 13: 114.
- Wieder JA, Brackett NL, Lynne CM et al: Anesthetic block of the dorsal penile nerve inhibits vibratory-induced ejaculation in men with spinal cord injuries. Urology 2000; 55: 915.
- Busato W and Galindo CC: Topical anaesthetic use for treating premature ejaculation: a double-blind, randomized, placebo-controlled study. British Journal of Urology, International 2004; 93: 1018.
- Dinsmore WW and Wyllie MG: PSD502 improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study. BJU Int 2009; 103: 940.
- Dinsmore WW, Hackett G, Goldmeier D et al: Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int 2006.
- Carson C and Wyllie M: Improved ejaculatory latency, control and sexual satisfaction when PSD502 is applied topically in men with premature ejaculation: results of a phase III, double-blind, placebo-controlled study. J Sex Med 2010; 7: 3179.
- Frink MC, Hennies HH, Englberger W et al: Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 1996; 46: 1029.
- Szkutnik-Fiedler D, Kus K, Balcerkiewicz M et al: Concomitant use of tramadol and venlafaxine - evaluation of antidepressant-like activity and other behavioral effects in rats. Pharmacol Rep 2012; 64: 1350.
- Salem EA, Wilson SK, Bissada NK et al: Tramadol HCL has promise in on-demand use to treat premature ejaculation. J Sex Med 2008; 5: 188.
- Kaynar M, Kilic O and Yurdakul T: On-demand tramadol hydrochloride use in premature ejaculation treatment. Urology 2011; 79: 145.
- Xiong GG, Wu FH, Chen SH et al: [Safety and efficacy of tramadol hydrochloride with behavioral modification in the treatment of premature ejaculation]. Zhonghua Nan Ke Xue 2011; 17: 538.
- Alghobary M, El-Bayoumy Y, Mostafa Y et al: Evaluation of tramadol on demand vs. daily paroxetine as a long-term treatment of lifelong premature ejaculation. J Sex Med 2010; 7: 2860.
- Bar-Or D, Salottolo KM, Orlando A et al: A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes. Eur Urol 2011; 61: 736.
- Eassa BI and El-Shazly MA: Safety and efficacy of tramadol hydrochloride on treatment of premature ejaculation. Asian J Androl 2013; 15: 138.
- Kirby EW, Carson CC and Coward RM: Tramadol for the management of premature ejaculation: a timely systematic review. Int J Impot Res 2015.
- Martyn-St James M, Cooper K, Kaltenthaler E et al: Tramadol for premature ejaculation: a systematic review and meta-analysis. BMC Urology 2015; 15: 6.
- Yang L, Qian S, Liu H et al: Role of tramadol in premature ejaculation: a systematic review and meta-analysis. Urol Int 2013; 91: 197.
- Wu T, Yue X, Duan X et al: Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis. Urology 2012; 80: 618.
- Cepeda MS, Camargo F, Zea C et al: Tramadol for osteoarthritis: a systematic review and metaanalysis. J Rheumatol 2007; 34: 543.
- Garrett PM: Tramadol overdose and serotonin syndrome manifesting as acute right heart dysfunction. Anaesth Intensive Care 2004; 32: 575.
- Mittino D, Mula M and Monaco F: Serotonin syndrome associated with tramadol-sertraline coadministration. Clin Neuropharmacol 2004; 27: 150.
- Takeshita J and Litzinger M: Serotonin syndrome associated with tramadol. Prim Care Companion, J Clin Psychiary 2009; 11: 273.
- McDiarmid T, Mackler L and Schneider DM: Clinical inquiries. What is the addiction risk associated with tramadol? J Fam Pract 2005; 54: 72.
- Adams EH, Breiner S, Cicero TJ et al: A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J Pain SymptomManage 2006; 31: 465.
- Lepor H: The evolution of alpha-blockers for the treatment of benign prostatic hyperplasia. Rev Urol 2006; 8 Suppl 4: S3.
- Debruyne FM: Alpha blockers: are all created equal? Urology 2000; 56: 20.
- Michel MC: Alpha1-adrenoceptors and ejaculatory function. Br J Pharmacol 2007; 152: 289.
- Kobayashi K, Masumori N, Hisasue S et al: Inhibition of Seminal emission is the main cause of anejaculation induced by a new highly selective alpha1A-blocker in normal volunteers. J Sex Med 2008; 5: 2185.
- Hisasue S, Furuya R, Itoh N et al: Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. Int J Urol 2006; 13: 1311.
- Cavallini G: Alpha-1 blockade pharmacotherapy in primitive psychogenic premature ejaculation resistant to psychotherapy. European Urology 1995; 28: 126.
- Basar MM, Yilmaz E, Ferhat M et al: Terazosin in the treatment of premature ejaculation: a short-term follow-up. International Urology & Nephrology 2005; 37: 773.
- Sato Y, Tanda H, Nakajima H et al: Silodosin and its potential for treating premature ejaculation: a preliminary report. Int J Urol 2012; 19: 268.
- Choi JH, Hwa JS, Kam SC et al: Effects of tamsulosin on premature ejaculation in men with benign prostatic hyperplasia. World J Mens Health 2014; 32: 99.
- Akin Y, Gulmez H, Ates M et al: Comparison of alpha blockers in treatment of premature ejaculation: a pilot clinical trial. Iranian red crescent medical journal 2013; 15: e13805.
- Furuya R, Hisasue S, Ogura H et al: [Ejaculatory disorder by alpha-1 adrenoceptor antagonist in patients with benign prostatic hyperplasia; retrospective comparison between naftopidil and tamsulosin]. Hinyokika Kiyo 2005; 51: 763.
- Bhat GS and Shastry A: Effectiveness of ‘on demand’ silodosin in the treatment of premature ejaculation in patients dissatisfied with dapoxetine: A randomized control study. Central European Journal of Urology 2016; 69: 280.
- Montague DK, Jarow J, Broderick GA et al: AUA guideline on the pharmacologic management of premature ejaculation. J Urol 2004; 172: 290.
- Abdel-Hamid IA, El Naggar EA and El Gilany AH: Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation. Int J Impot Res 2001; 13: 41.
- Chia S: Management of premature ejaculation -- a comparison of treatment outcome in patients with and without erectile dysfunction. Int J Androl 2002; 25: 301.
- Salonia A, Maga T, Colombo R et al: A prospective study comparing paroxetine alone versus paroxetine plus sildenafil in patients with premature ejaculation. J Urol 2002; 168: 2486.
- Erenpreiss J and Zalkalns J: Premature ejaculation: Comparison of patroxetine alone, paroxetine plus local lidocaine and paroxetine plus sildenafil. Int J Imp Res 2002; 14: S33:abstract PS
- Linn R, Ginesin Y, Hardak S et al: Treatment of sildenfil as part of the treatment in premature ejaculation. Int J Imp Res 2002; 14: S39:abstract P.
- Chen J, Mabjeesh NJ, Matzkin H et al: Efficacy of sildenafil as adjuvant therapy to selective serotonin reuptake inhibitor in alleviating premature ejaculation. Urology 2003; 61: 197.
- Li X, Zhang SX, Cheng HM et al: [Clinical study of sildenafil in the treatment of premature ejaculation complicated by erectile dysfunction]. Zhonghua Nan Ke Xue 2003; 9: 266.
- Lozano AF: Premature Ejaculation.Pharmacological treatment.Three years after. Int J Imp Res 2003; 15: S11: abstract MP.
- Tang W, Ma L, Zhao L et al: [Clinical efficacy of Viagra with behavior therapy against premature ejaculation]. Zhonghua Nan Ke Xue 2004; 10: 366.
- Zhang XS, Wang YX, Huang XY et al: [Comparison between sildenafil plus sertraline and sertraline alone in the treatment of premature ejaculation]. Zhonghua Nan Ke Xue 2005; 11: 520.
- McMahon CG, Stuckey B and Andersen ML: Efficacy of Viagra:Sildenafil Citrate in Men With Premature Ejaculation. J Sex Med 2005; 2: 368.
- Sommer F, Klotz T and Mathers MJ: Treatment of premature ejaculation: A comparative vardenafil and SSRI crossover study. J Urol 2005; 173: 202:abstract 741.
- Atan A, Basar MM, Tuncel A et al: Comparison of efficacy of sildenafil-only, sildenafil plus topical EMLA cream, and topical EMLA-cream-only in treatment of premature ejaculation. Urology 2006; 67: 388.
- Sun XZ, Deng CH and Dai YP: [A clinical study of sertralin and vardenafil in the treatment of premature ejaculation complicated by erectile dysfunction]. Zhonghua Nan Ke Xue 2007; 13: 610.
- Mattos RM, Marmo Lucon A and Srougi M: Tadalafil and fluoxetine in premature ejaculation: prospective, randomized, double-blind, placebo-controlled study. Urol Int 2008; 80: 162.
- Aversa A, Pili M, Francomano D et al: Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation. Int J Impot Res 2009; 21: 221.
- Mathers MJ, Klotz T, Roth S et al: Safety and efficacy of vardenafil versus sertraline in the treatment of premature ejaculation: a randomised, prospective and crossover study. Andrologia 2009; 41: 169.
- Jannini EA, McMahon C, Chen J et al: The controversial role of phosphodiesterase type 5 inhibitors in the treatment of premature ejaculation. J Sex Med 2011; 8: 2135.
- Mamas MA, Reynard JM and Brading AF: Nitric oxide and the lower urinary tract: current concepts, future prospects. Urology 2003; 61: 1079.
- McMahon CG, McMahon CN, Leow LJ et al: Efficacy of type-5 phosphodiesterase inhibitors in the drug treatment of premature ejaculation: a systematic review. BJU Int 2006; 98: 259.
- Asimakopoulos AD, Miano R, Finazzi Agro E et al: Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation? a systematic review and meta-analysis. J Sex Med 2012; 9: 2404.
- Martyn-St James M, Cooper K, Ren S et al: Phosphodiesterase Type 5 Inhibitors for Premature Ejaculation: A Systematic Review and Meta-analysis. Eur Urol Focus 2017; 3: 119.
- Li P, Zhu GS, Xu P et al: [Interventional effect of behaviour psychotherapy on patients with premature ejaculation]. Zhonghua Nan Ke Xue 2006; 12: 717.
- Mantovani F: Pharmacological/dynamic rehabilitative behavioural therapy for premature ejaculation: Results of a pilot study. Archivio Italiano di Urologia, Andrologia 2017; 89: 148.
- Pavone C, Abbadessa D, Gambino G et al: Premature ejaculation: Pharmacotherapy vs group psychotherapy alone or in combination. Archivio Italiano di Urologia, Andrologia 2017; 89: 114.
- Fein RL: Intracavernous medication for treatment of premature ejaculation. Urology 1990; 35: 301.
- Cooper K, Martyn-St James M, Kaltenthaler E et al: Interventions to treat premature ejaculation: a systematic review short report. Health Technology Assessment (Winchester, England) 2015; 19: 1.
- Sunay D, Sunay M, Aydogmus Y et al: Acupuncture versus paroxetine for the treatment of premature ejaculation: a randomized, placebo-controlled clinical trial. Eur Urol 2011; 59: 765.
- Sahin S, Bicer M, Yenice MG et al: A Prospective Randomized Controlled Study to Compare Acupuncture and Dapoxetine for the Treatment of Premature Ejaculation. Urol Int 2016; 97: 104.
- Cooper K, Martyn-St James M, Kaltenthaler E et al: Complementary and Alternative Medicine for Management of Premature Ejaculation: A Systematic Review. Sexual Medicine 2017; 5: e1.
- Simpson LL: The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol Rev 1981; 33: 155.
- Serefoglu EC and Silay MS: Botulinum toxin-A injection may be beneficial in the treatment of life-long premature ejaculation. Med Hypotheses 2010; 74: 83.
- Serefoglu EC, Hawley WR, Lasker GF et al: Effect of botulinum-A toxin injection into bulbospongiosus muscle on ejaculation latency in male rats. J Sex Med 2014; 11: 1657.
- Tuken M, Kiremit MC and Serefoglu EC: On-demand Modafinil Improves Ejaculation Time and Patient-reported Outcomes in Men With Lifelong Premature Ejaculation. Urology 2016; 94: 139.
- Carter CS: Oxytocin and sexual behavior. Neurosci Biobehav Rev 1992; 16: 131.
- de Jong TR, Veening JG, Olivier B et al: Oxytocin involvement in SSRI-induced delayed ejaculation: a review of animal studies. J Sex Med 2007; 4: 14.
- de Wied D, Diamant M and Fodor M: Central nervous system effects of the neurohypophyseal hormones and related peptides. Front Neuroendocrinol 1993; 14: 251.
- Hallbeck M, Larhammar D and Blomqvist A: Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord. J Comp Neurol 2001; 433: 222.
- Basal S, Goktas S, Ergin A et al: A novel treatment modality in patients with premature ejaculation resistant to conventional methods: the neuromodulation of dorsal penile nerves by pulsed radiofrequency. J Androl 2010; 31: 126.
- Kim JJ, Kwak TI, Jeon BG et al: Effects of glans penis augmentation using hyaluronic acid gel for premature ejaculation. Int J Impot Res 2004; 16: 547.
- Kwak TI, Jin MH, Kim JJ et al: Long-term effects of glans penis augmentation using injectable hyaluronic acid gel for premature ejaculation. Int J Impot Res 2008; 20: 425.
- Liu Q, Li S, Zhang Y et al: Anatomic Basis and Clinical Effect of Selective Dorsal Neurectomy for Patients with Lifelong Premature Ejaculation: A Randomized Controlled Trial. The Journal of Sexual Medicine 2019; 16: 522.
- Shi WG, Wang XJ, Liang XQ et al: [Selective resection of the branches of the two dorsal penile nerves for primary premature ejaculation]. Zhonghua Nan Ke Xue 2008; 14: 436.
- Anaissie J, Yafi FA and Hellstrom WJ: Surgery is not indicated for the treatment of premature ejaculation. Transl Androl Urol 2016; 5: 607.
- Alahwany A, Ragab MW, Zaghloul A et al: Hyaluronic acid injection in glans penis for treatment of premature ejaculation: a randomized controlled cross-over study. Int J Impot Res 2019; 31: 348.
- Sank LI: Traumatic masturbatory syndrome. J Sex Marital Ther 1998; 24: 37.
- Corona G, Jannini EA, Lotti F et al: Premature and delayed ejaculation: two ends of a single continuum influenced by hormonal milieu. Int J Androl 2011; 34: 41.
- Mulhall JP, Trost LW, Brannigan RE et al: Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol 2018; 200: 423.
- Giuliano F and Rowland DL: Standard operating procedures for neurophysiologic assessment of male sexual dysfunction. J Sex Med 2013; 10: 1205.
- Flannigan R, Heier L, Voss H et al: Functional Magnetic Resonance Imaging Detects Between-Group Differences in Neural Activation Among Men with Delayed Orgasm Compared with Normal Controls: Preliminary Report. J Sex Med 2019; 16: 1246.
- Mickle J, Milunsky A, Amos JA et al: Congenital unilateral absence of the vas deferens: a heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Human Reprod 1995; 10: 1728.
- Rowland D, van Diest S, Incrocci L et al: Psychosexual factors that differentiate men with inhibited ejaculation from men with no dysfunction or another sexual dysfunction. J Sex Med 2005; 2: 383.
- Perelman MA: 1254: Idiosyncratic Masturbation Patterns: A Key Unexplored Variable in the Treatment of Retarded Ejaculation by the Practicing Urologist. Journal of Urology 2005; 173: 340.
- Apfelbaum B: Retarded ejaculation: A much-misunderstood syndrome.: Guilford Press, 1989
- Nelson CJ, Ahmed A, Valenzuela R et al: Assessment of penile vibratory stimulation as a management strategy in men with secondary retarded orgasm. Urology 2007; 69: 552.
- Jenkins LC and Mulhall JP: Delayed orgasm and anorgasmia. Fertil Steril 2015; 104: 1082.
- Sadowski DJ, Butcher MJ and Kohler TS: A Review of Pathophysiology and Management Options for Delayed Ejaculation. Sex Med Rev 2016; 4: 167.
- Modell JG, May RS and Katholi CR: Effect of bupropion-SR on orgasmic dysfunction in nondepressed subjects: a pilot study. J Sex Marital Ther 2000; 26: 231.
- Abdel-Hamid IA and Saleh el S: Primary lifelong delayed ejaculation: characteristics and response to bupropion. J Sex Med 2011; 8: 1772.
- Landen M, Eriksson E, Agren H et al: Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1999; 19: 268.
- Bernik M, Vieira AH and Nunes PV: Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males. Rev Hosp Clin Fac Med Sao Paulo 2004; 59: 357.
- Arnott S and Nutt D: Successful treatment of fluvoxamine-induced anorgasmia by cyproheptadine. Br J Psychiatry 1994; 164: 838.
- Burri A, Heinrichs M, Schedlowski M et al: The acute effects of intranasal oxytocin administration on endocrine and sexual function in males. Psychoneuroendocrinology 2008; 33: 591.
- Walch K, Eder R, Schindler A et al: The effect of single-dose oxytocin application on time to ejaculation and seminal parameters in men. J Assist Reprod Genet 2001; 18: 655.
- Hollander AB, Pastuszak AW, Hsieh TC et al: Cabergoline in the Treatment of Male Orgasmic Disorder-A Retrospective Pilot Analysis. Sex Med 2016; 4: e28.
- Leduc BE, Fournier C, Jacquemin G et al: Midodrine in patients with spinal cord injury and anejaculation: A double-blind randomized placebo-controlled pilot study. J Spinal Cord Med 2015; 38: 57.
- Shoshany O, Abhyankar N, Elyaguov J et al: Efficacy of treatment with pseudoephedrine in men with retrograde ejaculation. Andrology 2017; 5: 744.
- Arafa M and El Tabie O: Medical treatment of retrograde ejaculation in diabetic patients: a hope for spontaneous pregnancy. J Sex Med 2008; 5: 194.
- Adeniyi AA, Brindley GS, Pryor JP et al: Yohimbine in the treatment of orgasmic dysfunction. Asian J Androl 2007; 9: 403.
- Balogh S, Hendricks SE and Kang J: Treatment of fluoxetine-induced anorgasmia with amantadine. J Clin Psychiatry 1992; 53: 212.
- MacDonald K and Feifel D: Dramatic improvement in sexual function induced by intranasal oxytocin. J Sex Med 2012; 9: 1407.
- IsHak WW, Berman DS and Peters A: Male anorgasmia treated with oxytocin. J Sex Med 2008; 5: 1022.
- Hsiao W, Deveci S and Mulhall JP: Outcomes of the management of post-chemotherapy retroperitoneal lymph node dissection-associated anejaculation. BJU Int 2012; 110: 1196.
- Yager J: Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report. J Clin Psychiatry 1986; 47: 210.
- Segraves RT: Reversal by bethanechol of imipramine-induced ejaculatory dysfunction. Am J Psychiatry 1987; 144: 1243.
- Paduch DA, Polzer PK, Ni X et al: Testosterone Replacement in Androgen-Deficient Men With Ejaculatory Dysfunction: A Randomized Controlled Trial. The Journal of Clinical Endocrinology & Metabolism 2015; 100: 2956.
- Leitner L, Guggenbuhl-Roy S, Knupfer SC et al: More Than 15 Years of Experience with Intradetrusor OnabotulinumtoxinA Injections for Treating Refractory Neurogenic Detrusor Overactivity: Lessons to Be Learned. Eur Urol 2016; 70: 522.
- Qu WM, Huang ZL, Xu XH et al: Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci 2008; 28: 8462.
- Ballon JS and Feifel D: A systematic review of modafinil: Potential clinical uses and mechanisms of action. J Clin Psychiatry 2006; 67: 554.
- Marson L, Yu G and Farber NM: The effects of oral administration of d-modafinil on male rat ejaculatory behavior. J Sex Med 2010; 7: 70.
- Ferraro L, Fuxe K, Tanganelli S et al: Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression. J Neurosci Res 2002; 68: 107.
- Ferraro L, Fuxe K, Tanganelli S et al: Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil. Neuropharmacology 2000; 39: 1974.
- Hull EM, Muschamp JW and Sato S: Dopamine and serotonin: influences on male sexual behavior. Physiol Behav 2004; 83: 291.
- Dominguez JM and Hull EM: Dopamine, the medial preoptic area, and male sexual behavior. Physiol Behav 2005; 86: 356.
- Carmichael MS, Humbert R, Dixen J et al: Plasma oxytocin increases in the human sexual response. J Clin Endocrinol Metab 1987; 64: 27.
- Uckert S, Becker AJ, Ness BO et al: Oxytocin plasma levels in the systemic and cavernous blood of healthy males during different penile conditions. World J Urol 2003; 20: 323.
- Stoneham MD, Everitt BJ, Hansen S et al: Oxytocin and sexual behaviour in the male rat and rabbit. J Endocrinol 1985; 107: 97.
- Arletti R, Bazzani C, Castelli M et al: Oxytocin improves male copulatory performance in rats. Horm Behav 1985; 19: 14.
- Arletti R, Benelli A and Bertolini A: Sexual behavior of aging male rats is stimulated by oxytocin. Eur J Pharmacol 1990; 179: 377.
- Gupta J, Russell RJ, Wayman CP et al: Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V(1A) receptors and not oxytocin receptors. Br J Pharmacol 2008.
- Argiolas A, Collu M, D'Aquila P et al: Apomorphine stimulation of male copulatory behavior is prevented by the oxytocin antagonist d(CH2)5 Tyr(Me)-Orn8-vasotocin in rats. Pharmacol Biochem Behav 1989; 33: 81.
- Clement P, Peeters M, Bernabe J et al: Brain oxytocin receptors mediate ejaculation elicited by 7-hydroxy-2-(di-N-propylamino) tetralin (7-OH-DPAT) in anaesthetized rats. Br J Pharmacol 2008; 154: 1150.
- Shinghal R, Barnes A, Mahar KM et al: Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study. Journal of Sexual Medicine 2013; 10: 2506.
- van de Waterbeemd H, Camenisch G, Folkers G et al: Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. . J Drug Target 1998; 6: 151.
- Muirhead GJ, Osterloh IH, Whaley S et al: Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects. J Sex Med 2019; 16: 213.
- McMahon CG, Osterloh IH, Rosen R et al: A phase IIA study to investigate the efficacy and safety of the selective oxytocin receptor antagonist, IX-01, in men with lifelong premature ejaculation. J Urol 2017; 1997: e1344.
- Althof S, Osterloh IH, Muirhead GJ et al: The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Phase IIb trial (PEDRIX). The Journal of Sexual Medicine 2019; 16: 1188.