International Society for Sexual Medicine's Guidelines for the Diagnosis and Treatment of Premature Ejaculation

Introduction

Over the past 20 years our knowledge of premature ejaculation (PE) has significantly advanced [1]. Specifically, we have witnessed substantial progress in understanding the physiology of ejaculation [2–8], clarifying the real prevalence of PE in population-based studies [9–13], reconceptualizing the definition and diagnostic criterion of the disorder [14], assessing the psychosocial impact on patients and partners [15], designing validated diagnostic and outcome measures [16], proposing new pharmacologic strategies, and examining the efficacy, safety, and satisfaction of these new and established therapies [17–21]. Given the abundance of high level research it seemed like an opportune time for the International Society for Sexual Medicine (ISSM) to promulgate an evidenced-based, comprehensive, and practical set of clinical guidelines for the diagnosis and treatment of PE.

We were able to identify three sets of clinical practice guidelines for the diagnosis and treatment of PE. They are the American Urological Association's 2004 Guidelines for the Pharmacologic Treatment of Premature Ejaculation, the European Association of Urology Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation, Updated 2009, and the Practice Guidelines for the Pan Arab Society of Sexual Medicine (Disorders of Ejaculation) [22–25]. It was our opinion that the existing guidelines were not sufficiently comprehensive, failed to adequately address both psychological as well as medical interventions and that essential new evidence that has come to light is not included in these documents. Therefore we undertook to develop a contemporary set of practical guidelines primarily targeting front line clinicians, and secondarily sexual medicine specialists.

Guideline Development Process

In September, 2009 the ISSM PE Guidelines Committee met in London for 3 days. The 26-committee members were selected by peer recommendation and further vetted to provide a diversity of discipline, balance of opinion, knowledge, gender and geography. These 22 men and 4 women included most of the world's highly recognized experts on PE and comprised ten urologists, five psychologists, three psychiatrists, two endocrinologists, two primary care physicians, one sexual medicine physician, one genitourinary physician, one internal medicine physician, and one radiation oncologist. The committee was chaired by Stanley Althof, PhD and the meeting facilitated by ISSM President, John Dean, MD. All members were required to declare in advance any potential conflicts of interest with their participation in the committee's work.

A comprehensive review of scientific literature on PE was conducted by ISSM research assistants under the supervision and guidance of the Chairman. Selected original articles were circulated to committee members prior to meeting. Committee members were invited to review all available evidence, not just the articles provided by the ISSM researchers, and prepare a presentation for the meeting on specific topics related to the guidelines. The committee utilized evidence-based medicine grading as the means of integrating individual clinical expertise with the best available external clinical evidence from systematic research. Where available, evidence of important outcomes was collated for each sub-population. Quality of evidence, and the strength of any recommendation was graded using the Oxford Centre of Evidence-Based Medicine system [26]. Figure 2 contains a summary of the relevant evidence-based recommendations of the Committee.

The meeting was supported by an unrestricted grant from Johnson and Johnson, the manufacturer of dapoxetine. However, ISSM required complete independence from industry during the development of the guideline and related resources. There were no industry representatives at the meeting and there was no attempt by industry to influence any part of the development or writing process at any time.

Definitions of PE

Several definitions for PE exist having been crafted by various professional organizations and/or individuals [11,25,27–31] (see Table 1). Most of these definitions include the subtypes of lifelong and acquired (PE symptoms beginning after a period of normal ejaculatory function). The major criticisms of the existing definitions included their failure to be evidenced-based, lack of specific operational criteria, excessive vagueness, and reliance on the subjective judgment of the diagnostician. Nonetheless, three common constructs underlie most definitions of PE: (i) a short ejaculatory latency; (ii) a lack of perceived self-efficacy or control about the timing of ejaculation; and (iii) distress and interpersonal difficulty (related to the ejaculatory dysfunction).

Because of the discontent with the existing definitions of PE, as well as pressure from the regulatory agencies concerning the inadequacy of the PE definitions, the ISSM convened in 2007 a meeting of experts to review the evidence-based literature and to develop a definition grounded in clearly definable scientific criteria [14]. After carefully reviewing the literature, the Committee proposed that lifelong PE is,

The definition applies only to intravaginal sexual activity. It does not define PE in the context of other sexual behaviors or men having sex with men. The Committee concluded that there is insufficient information available to extend the definition of PE to these other groups. Additionally, the Committee concluded that there are insufficient published objective data to propose a new evidence-based definition of acquired PE, although it believed the proposed criterion for lifelong PE might be applied to acquired PE as well.(LOE 5d)

Anteportal ejaculation is the term for men who ejaculate prior to vaginal penetration and is considered the most severe form of PE. Such men/couples typically present when they are having difficulty conceiving children. It is estimated that 5% of lifelong PE men suffer from anteprotal PE [18,32,33].

Although not evidenced based, Waldinger proposed two additional “subtypes” for men who are distressed about their ejaculatory function but do not meet the ISSM criterion for PE [31]. These subtypes should be considered provisional; however, we thought it was important to include them because they accurately characterize many men who do not qualify for the diagnosis of PE and are asking for help. We believe these categories may help health-care professionals (HCPs) address these men's concerns.

These two subtypes are termed natural variable PE and premature-like ejaculatory dysfunction. Natural variable PE is characterized by early ejaculations which occur irregularly and inconsistently with some subjective sense of diminished control of ejaculation. This subtype is not considered a sexual dysfunction or psychopathology but rather a normal variation in sexual performance.

Premature-like ejaculatory dysfunction is characterized by: (i) subjective perception of consistent or inconsistent rapid ejaculation during intercourse; (ii) preoccupation with an imagined early ejaculation or lack of control of ejaculation; (iii) actual intravaginal ejaculation latency time (IELT) in the normal range or even of longer duration (i.e., an ejaculation that occurs after 5 minutes); (iv) ability to control ejaculation (i.e., to withhold ejaculation at the moment of imminent ejaculation) may be diminished or lacking; and (v) the preoccupation is not better accounted for by another mental disorder [34]. (LOE 5d)

Prevalence

Reliable information on the prevalence of lifelong and acquired PE in the general male population is lacking. Confounding accurate prevalence estimates are the competing and varying definitions of PE and the manner in which prevalence data was gathered (population-based, self-report, or clinician based). Local and regional variations should be considered in the context of different cultural, religious, and political influences. Additionally, prevalence may vary across different demographics, including geography, ethnicity, and social status [11].

Based on patient self-report, PE is routinely characterized as the most common male sexual dysfunction. Prevalence data derived from patient self-report will be appreciably higher than prevalence estimates based on clinician diagnosis utilizing the more conservative ISSM definition of PE. The following studies demonstrate the varying prevalence estimates ranging from 30% down to 3%.

Data from The Global Study of Sexual Attitudes and Behaviors (GSSAB), an international survey investigating the attitudes, behaviors, beliefs, and sexual satisfaction of 27,500 men and women aged 40–80 years, reported the global prevalence of PE (based on subject self-report) to be approximately 30% across all age groups [9,12]. Perception of “normal” ejaculatory latency varied by country and differed when assessed either by the patient or their partner [35].

Differing from the GSSAB study, the Premature Ejaculation Prevalence and Attitude Survey found the prevalence of PE among men aged 18 to 70 years to be 22.7% [10]. PE was categorized by subject self-report. Prevalence was similar across countries (24.0% in the United States, 20% in Germany and Italy) and age groups. Similar results by age groups were also found by Brazilian Sexual Life Study, and PE was reported in 25.8% of 3,332 Brazilian men [36].

A Canadian study, using a study-specific definition of PE, based largely on the Diagnostic and Statistical Manual of Mental Disorders (DSM) III criteria (those who had fair/to poor control over their ejaculation and claimed that time to climax was a problem for them or their partner), classified 16% of males aged 18 to 60 years and above as experiencing PE [37]. Consistently lower rates of PE were reported by female partners, ranging between 9% and 14%.

Applying only the time parameter (IELT approximately 1 minute) of the ISSM definition of PE to a population-based cohort of 500 men with stopwatch measured IELTs, only 1–3% would be eligible for the diagnosis [38,39]. These men were not given measures to assess control or distress. The 1–3% prevalence is considerably different from the previous prevalence estimates of 20–30% based on self-report or DSM-III diagnosis. The lower prevalence estimates are more consistent with the numbers of men who present for treatment of PE. However, even though some men who present for evaluation of PE will not meet the ISSM diagnostic criteria they should be carefully evaluated and considered for appropriate treatment.(LOE 3b)

Etiology

Over the past two decades several studies have suggested that lifelong and acquired PE may be caused by somatic disorders and/or neurobiological disturbances. Previously it was thought that the condition was primarily psychologically or interpersonally based. Examples of these biological factors include: hypersensitivity of the glans penis [41], a higher cortical representation of the pudendal nerve [42], disturbances in central serotonergic neurotransmission [43,44], erectile difficulties [45], prostatitis [46,47], detoxification from prescribed drugs (e.g., raboxetine [48], citalopram [49]) or recreational drugs [49,50], chronic pelvic pain syndrome [51], varicocele [52], and thyroid disorders [53,54]. It is noteworthy that none of these “organic” etiologies has yet been supported by robust and large-scale studies.

Recent studies have suggested that in some men neurobiological and genetic variations could contribute to the pathophysiology of lifelong PE, as defined by the ISSM criteria and that the condition may be maintained and heightened by psychological/environmental factors [55,56]. In animal experiments serotonin receptors have been implicated in the etiology of lifelong PE and partly in acquired PE. Waldinger et al. hypothesized that lifelong early ejaculation in humans may be explained by either a hyposensitivity of the 5-HT2C and/or hypersensitivity of the 5-HT1A receptors [57]. They hypothesized that men with a low 5-HT neurotransmission and probable 5-HT2C receptor hyposensitivity may have their ejaculatory threshold genetically set at a lower point and ejaculate quickly with minimal stimulation. Additionally, in rapidly ejaculating rats, it has been recently demonstrated that the spinal command of ejaculation differs when compared with “normal” rats [58]. Serotonin dysregulation as an etiological hypothesis for PE may explain only a small percentage (2–5%) of complaints of PE in the general population [55].

Quality of Life Impact of PE on the Man and Partner

Eleven observational, non-interventional studies from 1997 to 2007 were reviewed that report on the psychosocial and quality of life consequences of PE on the man, his partner and the relationship [15]. These studies employed different methodologies, outcome measures, and consisted of both qualitative and quantitative investigations. All studies consistently confirmed a high level of personal distress reported by men with PE and their female partners. The negative impact on single men with PE may be greater than on men in relationships as it serves as a barrier to seeking out and becoming involved in new relationships [75]. Men with PE have significantly lower scores on self-esteem and self-confidence than non-PE men and one-third of men with PE report anxiety connected to sexual situations [76]. It may seem obvious but PE has a direct negative influence on women's sexual experience [10,77]. Both men and their partners affirm negative effects and interpersonal difficulty related to their PE and an overall reduction in their quality of life [15,76,78].(LOE 1a–3a)

Should Clinicians Specifically Screen for PE

Screening involves testing of a symptomless population in order to detect cases of a disease at an early stage. Clearly, men affected by PE are not symptomless and, for PE, case-finding might be a better term.

The committee agreed that there was inadequate evidence to recommend screening or case-finding for PE, either in a general population or in most sub-populations. However, it is recommended that men with ED be screened for PE.(LOE 5d)

Improvements in public awareness of sexual health issues, including PE, are required, so that individuals affected by sexual concerns are aware of options and interventions open to them. Physicians have an important role to play in sexual health education and PE should be included within sexual health education programs.

Assessment of PE

History

Patients expect clinicians to inquire about their sexual health [79]. Often patients are too embarrassed, shy, and uncertain if sexual complaints belong in the HCP's office [80]. Inquiry into sexual health gives patients permission to discuss their sexual concerns and also screens for associated health risks (e.g., cardiovascular risk and ED).

Table 2 lists recommended and optional questions that patients who complain of PE should be asked [81]. The recommended questions establish the diagnosis and direct treatment considerations and the optional questions gather detail for implementing treatment. Finally, the committee recommends that the HCPs take a medical and psychosocial history. (LOE 5d)

Table 2. Recommended and optional questions to establish the diagnosis of PE and direct treatment

Recommended questions For diagnosis	What is the time between penetration and ejaculation (cumming)?
	Can you delay ejaculation?
	Do you feel bothered, annoyed, and/or frustrated by your premature ejaculation?
Optional questions Differentiate lifelong and acquired PE	When did you first experience premature ejaculation?
	Have you experienced premature ejaculation since your first sexual experience on every/almost every attempt and with every partner?
Optional questions Assess erectile function	Is your erection hard enough to penetrate?
	Do you have difficulty in maintaining your erection until you ejaculate during intercourse?
	Do you ever rush intercourse to prevent loss of your erection?
Optional questions Assess relationship impact	How upset is your partner with your premature ejaculation?
	Does your partner avoid sexual intercourse?
	Is your premature ejaculation affecting your overall relationship?
Optional question Previous treatment	Have you received any treatment for your premature ejaculation previously?
Optional questions Impact on quality of life	Do you avoid sexual intercourse because of embarrassment?
	Do you feel anxious, depressed, or embarrassed because of your premature ejaculation?

Figure 1 is a flowchart devised by Rowland et al. detailing the assessment and treatment options for subjects complaining of PE [1].

Assessment of Ejaculatory Latency

Treatment

Outcome

Across all treatments, including daily and as-needed dosing schedules patient's IELT may be expected to increase between three- to eightfold compared with baseline IELT. Similarly, patient's perceived control (self-efficacy) of their ejaculatory timing was significantly improved with treatment. From the patient's perspective, perceived ejaculatory control was a more important outcome variable than IELT alone [150].

Treatment outcome can be addressed in one simple, brief, and validated question known as the Clinical Global Impression of Change (CGIC) [151]. It asks patients, “Compared to before starting treatment, would you describe your PE problem as: much worse, worse, slightly worse, no change, slightly better, better, or much better?”(LOE 1b)

In randomized, placebo-controlled, double-blind trials of dapoxetine for each category of improvement on the CGIC, the magnitude of IELT prolongation increased in concert with the CGIC rating. Additionally, significant positive correlations were noted between CGIC ratings and ejaculatory control and sexual satisfaction and inverse correlation were noted with sexual distress. Control accounted for the greatest proportion of the variance of the CGIC.

Role of the Primary Care Clinician (PCP)

Primary care providers are usually the first line of contact for a patient with the health care system including the diagnosis and treatment of sexual problems. This role includes: (i) initial recognition and evaluation of any undiagnosed sign, symptom, or health concern (the “undifferentiated” patient); (ii) health promotion including disease prevention, health maintenance, counseling, patient education, chronic illness management, and patient advocacy; and (iii) coordination of care promoting effective communication with patients and encouraging the patient to be a partner in health [152]. This model of care is not limited by problem origin, organ system, or diagnosis.

Primary care clinicians are the ideal group to assist the patient with sexual difficulties for several reasons including: (i) the value of the longitudinal and personal relationships with patients in discussing and resolving sexual problems; (ii) the multifactorial issues around sexual problems that can be appropriately evaluated by a generalist clinician; and; (iii) the long-term follow-up routine in primary care is well-suited to being certain that a sexual dysfunction is resolved. The main obligation of the PCP is to recognize PE and make the patient feel comfortable about getting help. Initial work-up and treatment can be planned by the PCP who has good communication skills about sexual activity and who is knowledgeable about first-line treatments. Urologists can be helpful in difficult or complex situations. A mental health professional with experience in sexual problems collaboratively with the clinician increases the chances of therapeutic success by: (i) resolving the sexual difficulty; (ii) teasing out important history; (iii) educating the patient and partner; (iv) suggesting sexual enhancement techniques; and (v) helping the couple resolve individual as well as relationship problems.

Help from a sexual health specialist may be appropriate at varying intervals when managing a man with PE. The major factors in determining when a consultation is needed include (i) the primary care clinician's comfort in discussing and managing treatment options; (ii) the depth of the psychosocial and sexual issues involved; and (iii) the success or failure of the initial intervention efforts. Specific instances in which subspecialty assistance is often useful include (i) treatment failure; (ii) anatomic or complex hormonal issues; (iii) complex issues around sex and/or partnerships; (iv) severe psychological problems; or (v) anytime the treating physician feels that help is needed.

The management algorithm “ALLOW” an outgrowth of the PLISSIT model (permission, limited information, specific suggestions and intensive therapy) [153] can help PCPs talk with their patients about sexual health problems and refer patients when appropriate [154]. The physician begins by “Asking” about a patient's sexual life and “Legitimizes” the importance and potential impact of sexual problems to the patient. The physician then considers his/her “Limitations” with regard to managing the sexual dysfunction, and may refer the patient to a sexual health specialist for further evaluation and management. Conversely, if the physician feels comfortable managing the patient's issue(s), he/she then “Opens: up the issue(s) for further discussion,” and the physician and the patient “Work together to develop a management plan.” This methodical approach to “allowing” the patient to discuss sexual issues can be accomplished in as brief or as long a time as the physician has available.

When a clinical situation is encountered in which the primary care clinician needs assistance in management, two options are available. Patients can be sent to a sexual health specialist for a “consultation.” This is a request to answer a specific question with the intention that management will be advanced under the primary care clinician considering the added input. The second option is “referring” the patient to another clinician, usually a sexual health specialist to move further with management. In these situations, a summary of the reason for referral, appropriate history, and related diagnostic studies should accompany the patient. The sexual health specialist will then appropriately advance the management keeping the primary care clinician advised of progress. In a “referral” the care for the referred patient is usually transferred to the sexual health specialist. Communication can be enhanced by the primary care clinician by specifically informing the sexual health specialist about the level of involvement requested [155].

Co-management by the less experienced primary care clinician along with an appropriate sexual health specialist is an excellent way to manage the patient's issues and to increase the primary care clinician's understanding of PE. Good communication between clinicians can improve patient outcome and understanding of planned treatments and monitoring measures. Co-management can be optimized by a clear understanding between the primary care clinician and the sexual health specialist about who will do what. This kind of communication can be ensured by creating “referral agreements” in which a specific referral guideline is used and the responsibilities and activities of each clinician are clearly spelled out [156].

Conclusion

These guidelines have been carefully promulgated by an interdisciplinary international panel of recognized experts in the area of PE with the goal of constructing clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Recognizing that all evidence is not created equal the Committee reviewed and debated the research literature to arrive at its grading of their recommendations according to the Oxford Centre of Evidence-Based Medicine rankings.

Figure 2 lists all the relevant recommendation of the PE Guidelines Committee. These Guidelines affirm the ISSM definition of PE and suggest that the prevalence is considerably lower than previously thought. Evidence-based data regarding biological and psychological etiology of PE are presented, as is population-based statistics on normal ejaculatory latency. Brief assessment procedures are delineated and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients.

Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. Therefore, it is strongly recommended that these guidelines be re-evaluated and updated by the ISSM every 4 years.

Finally, it is important to keep in mind that PE causes significant personal and interpersonal distress to the man, his partner and the couple. We are hopeful that these guidelines will assist clinicians in accurately diagnosing and managing their patients who present with complaints of PE.

Conflict of Interest: Dr. Althof is a Principal Investigator for Boehringer Ingelheim, Johnson and Johnson and United Biosource. He is also a Consultant to Johnson and Johnson, Eli Lilly, Palitan and Shionogi. He serves on Advisory Boards for Boehringer Ingelheim, Neuohealing, and Shionogi. He is a speaker for Boehringer Ingelheim and Shionogi. Dr. Abdo is an Investigator for Eli Lilly, Janssen Cilag and Pfizer. She serves on Advisory Boards for Boehringer Ingelheim, Eli Lilly, Janssen Cilag and Pfizer. Dr. Abdo is a speaker for Eli Lilly, GlaxoSmithKline, Janssen Cilag and Pfizer. Dr. Dean is an Investigator, Consultant and Speaker for Bayer Schering, Johnson & Johnson, Eli Lilly, Pfizer, Plethora, Proctor & Gamble, Pro-Strakan and Shionogi. Dr. Hackett is a speaker for occasional speaker for Eli Lilly, Bayer and Boehringer-Ingleheim. Dr. McCabe is on the Advisory Boards for Pfizer, Bayer, Eli Lilly and Janssen Cilag. Dr. McMahon is Investigator, Advisory Board Member and/or Speaker for Janssen Cilag, Bayer Schering, Ausio and Auxilium. Dr. Rosen is a Consultant to Boehringer Ingelheim, Eli Lilly, Endo, Johnson and Johnson, and Ferring. Dr. Sadovsky is a Consultant for Eli Lilly and Boehringer-Ingelheim. Dr. Waldinger is an Investigator for GlaxoSmithKline and Dong-A Pharmaceuticals. Dr. Becher is an Investigator for Janssen Cilag Argentina. Dr. Broderick receives Grant and Research support from Johnson and Johnson, Vivus, Medtronic and Wilex. Dr. Buvat is an Investigator, Advisor and Speaker for Bayer Schering, Boehringer Ingelheim, Biovail, Janssen/Cilag and Johnson and Johnson, Lilly and Strakan. Dr. El-Meliegy serves on Advisory Boards for Bayer Schering and Eli Lilly. He is also a speaker for Pfizer, Bayer Schering and Eli Lilly. Dr. Giuliano is an Investigator for Pfizer and Bayer. He is a Consultant to Johnson and Johnson, Pfizer, Bayer Schering, Sanofi-Aventis and Lilly. He serves as a speaker for Johnson & Johnson, Pfizer and Lilly. Dr. Goldstein receives research funding from Astellas, Auxillium, Biosante, Boehringer Ingelheim, Endoceutics, GSK, Medtronic, Pfizer and Vivus. He is a Consultant to Alogan, Fabrey Kramer, Trimel and Vivus. He serves on the Advisory Board for Boehringer Ingelheim, Medtronic, Neocutis, Shinonogi and Slate. He is a speaker for Abbott, Auxillium, Boehringer Ingelheim, Coloplast, Slate and Vivus. Dr. Helstrom is an Investigator for Auxilium, Coloplast, Endo, GSK/Shering Plough/Bayer, Johnson and Johnson, Sanofi-Aventis, Shionogi, Vivus. He is also a Consultant to American Medical Systems, Auxilium, Boehringer Ingelheim, Coloplast, Endo, GSk/Sherring Plough/Bayer, Johnson and Johnson, Medtronic, Sanofi Aventis, Slate, Solvay and Vivus. He is a speaker for Auxilium, GSK/Sherring Plough/Bayer, Johnson and Johnson, Medtronic, and Solvay. He is a Board Member, Officier and Trustee of NIH and Theralogix. Dr. Jannini is an Investigator, Consultant and Speaker for Bayer Schering, Janssen-Cilag, Eli Lilly and Pfizer. Dr. Parish is a Consultant, serves on the Advisory Board and Speaker's Bureau for Boehringer Ingelheim. Dr. Park is a Principal Investigator and serves on the Advisory Board for Priligy, Korea. Dr. Porst serves as an Investigator, Consultant and Speaker for Johnson & Johnson, Janssen-Cilag, Eli Lilly and Bayer. Dr. Seagraves is a Consultant to Boehringer Ingelheim and Transtech. Dr. Sharlip is a Consultant, Member of the Speakers Bureau and Advisory Board for Boehringer Ingenheim, Eli Lilly, Johnson and Johnson, Pfizer, Plethora Solutions and Shionogi.

Drs. Incrocci, Rowland, Simonelli, and Tan have no conflicts to disclose.

Statement of Authorship