Premature ejaculation: challenging new and the old concepts

Introduction

Premature ejaculation (PE) is a complex and poorly understood condition which can be difficult to manage for both the clinician and the patient. In this review, we will challenge some of the accepted theories and treatments associated with this condition and explore the current management options and potential treatments.

Does the concept of early ejaculation exist?

Mammals ejaculate quickly to enhance their ability to procreate with multiple partners and spread their genetic material. In humans, sexual intercourse not only allows us to fulfil our reproductive potential but also has important effects on our quality of life. As boys reach puberty and start engaging in sexual activity, their time to ejaculation and their perceived control over their ejaculation change over time¹. We accept this to be a normal part of sexual maturity; however, we may define the same features as a sign of PE in an adult. In addition, ejaculation control and time are dependent on the male, his partner, and the sexual situation^2–4. Early ejaculation is not necessarily always associated with lack of sexual enjoyment, and the perception of a sexual dysfunction secondary to PE may be heavily influenced by social factors^5–7. We also know that social media, cultural attitudes, and abstinence can all affect sexual function^5–7. Therefore, defining PE as a pathological condition may not necessarily be correct. We should use these concepts to challenge whether PE truly exists or whether it has arisen as a result of men having unrealistic concepts of sexual function which are based on social conditioning, especially the use of pornography. PE is a multimillion-dollar industry and therefore the pharmaceutical industry must be challenged as to whether medicalising PE benefits our patients or whether they would be best served with psycho-sexual counselling¹. In addition, the literature rarely assesses or medicates the female partners.

Prevalence

PE is estimated to affect 20–40% of the general population, although only 4–5% may fulfil the International Society of Sexual Medicine (ISSM) definition for this^8–13. Nathan et al. reported a prevalence of 35% based on the Diagnostic and Statistical Manual of Mental Disorders, third edition, Text Revision (DSM-III-TR) definition³. In an Italian telephone survey, 14.7% of the calls were regarding PE and peak age was 26–35 years¹⁴. Women called less frequently about PE. Similar results were obtained from a study on subjects contacting a UK-based sexual advice charity by email or telephone². Although most visitors to the charity’s website were from the UK, significant proportions were from the USA, Singapore, Canada, and India. PE was reported by 16% contacting the charity, and the peak age in men was 31–40 years old². PE was more commonly reported by men outside the UK, especially from the Indian subcontinent. The huge variability in the reported prevalence is due to the different methods with which PE is defined, which include questionnaires, self-reports, and several expert panel definitions^8–11. Despite the variability in reported prevalence rates, a consistently lower proportion of men seek treatment^15,16. This may reflect embarrassment and the perceived stigma attached to the condition.

Physiology

Ejaculation is a normal part of male sexual function and consists of two coordinated neurological reflexes: emission and ejection¹⁷. Orgasm is separate but occurs simultaneously¹⁸. Emission involves contractions of the seminal vesicles and prostate and results in expulsion of sperm and seminal fluid into the posterior urethra¹⁹. This is mediated by the sympathetic nervous system (T10–L2). Ejection involves the pulsatile contractions of the bulbocavernosus and pelvic floor muscles with relaxation of the external urinary sphincter¹⁹. This is mediated by somatic nerves (S2–4) and involves the sympathetic nervous system with limited voluntary control¹⁹. These reflexes are stimulated by sensory input from nerve endings in the glans penis, which are relayed via the sacral spinal cord to the sensory cerebral cortex¹⁷. The pathway involves central serotonergic and dopaminergic neurons with secondary involvement of cholinergic, adrenergic, oxytocinergic, and gamma aminobutyric acid (GABA) neurons¹⁹.

Dopamine and serotonin are essential neurotransmitters; dopamine promotes seminal emission and ejaculation via D2 receptors, while serotonin is inhibitory via the serotonin receptors (5-HT)¹⁹. Stimulation of the 5-HT_2c receptor results in ejaculatory delay in rats, whereas stimulation of the post-synaptic 5-HT_1A receptors results in shortening of ejaculatory latency time^8,19. It has been postulated that PE is due to hyposensitivity of 5-HT_2C or hypersensitivity of 5-HT_1A receptors or both. The role of oxytocin is less well established and has been found to have a stimulatory effect on ejaculation in rat models and reduces ejaculatory latency times^8,20. This may be as a result of modulating the action of the 5-HT_1A receptors²¹.

The influence of hormones is less clear. Some animal models have suggested that cerebral dopamine and serotonin may interact with the hypothalamic-pituitary-thyroid axis^22–24. Hyperthyroid rats were found to have shorter times to first ejaculation compared with controls²⁵. A small study by Carani et al. found a significant correlation between PE and hyperthyroid men, which fell dramatically, from 50 to 15%, following treatment²⁶. This would support a possible role for the thyroid hormones in ejaculation. However, other studies have suggested that there is a role only in acquired PE and this is a rare cause^27,28.

A growing area in the aetiology of PE is its possible association with prostatitis. Sereponi et al. investigated the prevalence of chronic prostatitis in 46 men with PE and compared this group with an age-matched group of 30 healthy men²⁹. Prostatic inflammation and chronic bacterial prostatitis were found in 56.5% and 47.5% (respectively) of men with PE. In addition, 28.2% with PE were found to have one or more clinical symptoms of prostatitis. This study has been followed by several studies which have reviewed the effect of treating prostatitis on PE^30,31. Treatment of prostatitis with a month of antibiotics based on culture sensitivities appears to increase ejaculatory latency times (2.6-fold) and control over ejaculation (83.9%)^30,31. There was no recurrence of PE at a follow-up of 4 months^30,31. Antibiotics appear to be most effective in men with acquired PE and where there are at least 19 pus cells per high-powered field in expressed prostate secretions³¹. The mechanism remains poorly understood, but it has been suggested that prostatic inflammation may alter sensation and therefore the ejaculatory reflex³². Although the evidence may still be growing, the assessment of the prostate appears to be a useful adjunct to the management of PE. However, as always, we must balance our use of antibiotics with our responsibility as antibiotic stewards in the growing international antibiotic crisis.

How to define premature ejaculation

Early definitions of PE were criticised for their inconsistency and often having vague definitions subject to the clinician’s interpretation^33,34. This has led to heterogeneous studies, adversely affecting both research and valid information regarding prevalence of the condition^33,34. In 1980, the American Psychiatric Association published the DSM-III-TR, which has clearly defined PE albeit with many flaws³⁵. This definition (Table 1) has been revised several times, and the current, fifth edition has corrected much of the earlier ambiguity (Table 1)³⁶.

This definition remains largely contentious with many ongoing criticisms. The absence of time criteria in the definition opens it up to misinterpretation by clinicians. This leads to inconsistencies in data collection and difficulty making direct comparisons between studies because of heterogeneous patient populations. This is illustrated by two studies using the DSM-V-TR definition (unchanged from version IV), which revealed significant overlap between the group defined as having PE and the group without PE^37–40. A total of 13–25% of men with a diagnosis of PE according to the definition had intravaginal latency times of 4–25 minutes. In the study by Giuliano et al., 12.1% defined as not having PE had intravaginal latency times of less than 2 minutes³⁹.

A further criticism of the definition is that clinicians are asked to consider factors which may affect the excitation phase, such as age³³. However, there is no consistent evidence that age, novelty of partner, or relationship duration has any effect on ejaculatory latency times^41,42. In a large global phone and email survey, men younger than 40 were significantly more likely to report PE². However, in a study of sexual behaviours and attitudes in the USA, the reverse was found⁴.

The last major criticism is the absence of criteria for how frequently or the duration over which rapid ejaculation should occur before it may be defined as problematic³³. A man with frequent sexual engagement who occasionally experiences rapid ejaculation may not be bothered, whereas a man with infrequent sexual opportunity may be bothered by a single episode of rapid ejaculation. The definition does not clarify which subject should be diagnosed as having PE. The ISSM convened a panel of international experts to produce a new evidence-based definition (see Table 2^13,43,44 for the current one) which would address most of the inconsistencies of earlier definitions.

The main difficulties with this definition are the method of measuring the latency time and how to define a normal or abnormal time. The concept of the intravaginal ejaculatory latency time (IELT) was introduced by Waldinger et al.^5,45 in 1994. This is the time from vaginal penetration to ejaculation. It is a useful measurement tool in PE studies and may be either estimated by the male or his partner or measured directly with the use of a stopwatch. Several studies have suggested an acceptable correlation between estimated times^46,47. There was a tendency for men to overestimate their IELT^6,46,47. This would allow the use of estimated IELT measures in clinical practice instead of measured IELT which may not be practical for couples. However, the study by Pryor et al., which compared, estimated, and measured IELTs, based PE definition on the DSM-IV-TR criteria, which is an inherent flaw in the study⁴⁶. This suggests that the estimated and measured IELTs are equivocal and erroneous, and we may need to repeat studies using the ISSM definitions for PE. Two large international population studies have provided useful information on IELT in the general population^5,6. Both revealed a positively skewed distribution in IELT, and median times were 5.4 minutes (range of 0.55–44.1) and 6 minutes (range of 0.1–52.7). There was significant variability across the countries involved. This may suggest that IELT definitions need to be adjusted depending on the ethnic mix of the study population. In addition, it provides a useful counselling tactic to reassure a male patient that he is actually within the normal distribution. However, studies which have analysed IELT in the general population have not included ethnically diverse populations. A study from the UK reported that the highest incidence of PE was in men from Asian and Islamic backgrounds, which may reflect a genetic or a cultural aetiology⁷. More studies are required to define normal IELT in these populations.

The first study revealed a significant reduction in IELT with age:

The use of the 0.5 and 2.5 percentile is an accepted method of defining disease within a skewed distribution⁴⁸. These two studies, therefore, have defined an abnormal IELT as being 1 minute^5,7,46. This has been incorporated within the ISSM PE definition⁴⁴ and has been supported in PE studies where 77–92% of men with PE generally ejaculate within 60 seconds^47,49,50.

The use of IELT is not without inherent problems. The data collected using IELT are usually based on either men with lifelong PE (LPE) or heterosexual men within stable relationships engaging only in vaginal penetrative sexual intercourse³³. This limits its general applicability to clinical populations. In addition, the act of measuring ejaculatory latency itself may affect sexual performance either positively or negatively. This is a factor which may be difficult to account for or quantify within clinical trials or medical practice.

The European Association of Urology (EAU) guidelines mention both definitions; however, it recommends that the diagnosis of PE include self-estimated IELT, perceived control, and interpersonal difficulty due to ejaculatory dysfunction⁵¹. The American Association of Urology mentions the DSM-IV-TR in its discussion on PE definitions⁵². However, it defines PE as “ejaculation that occurs sooner than desired, either before or shortly after penetration, causing distress to either one or both partners”⁵².

Validated questionnaires

Several validated questionnaires, which are mainly for use in clinical trials, have been developed^53–56. Whilst they are useful adjuncts in clinical assessment and measuring the impact of treatment on PE, they are not without limitations, and they are used to assess LPE and men who have vaginal sexual intercourse⁵⁷. Currently, the EAU guidelines for PE recommend that both stopwatch-measured IELT and these types of questionnaire are not used in clinical practice⁵¹.

Management options: historical options

The current EAU guidelines for the management of PE suggest the use of pharmacotherapy as first-line treatment⁵¹. This includes either the short-acting dapoxetine (DPX) on demand or other off-label antidepressants such as daily selective serotonin reuptake inhibitors (SSRIs). Tramadol and topical local anaesthetics may be used as weak alternatives to SSRIs; phosphodiesterase-5 inhibitors (PDE5is) should be used only in men with concomitant ED⁵¹. Behavioural therapy should be used with pharmacotherapy (Table 4)^60,61.

Behavioural therapy

The aim of behavioural therapy is the development of sexual skills over time, which allows the male to delay ejaculation, increase sexual confidence, and reduce performance anxiety or stress⁶¹. There are two types of behavioural therapy: psychotherapy and physical techniques⁶².

Psychotherapy uses counselling to identify and correct any interpersonal problems, which may have precipitated or be contributing to PE^8,62. Physical therapies involve a variety of exercises to slowly increase the degree of genital stimulation over time, which allows the male to gain control over his ejaculation^8,62. This includes ‘stop-start’, ‘squeeze’, ‘sensate focus’, and pelvic floor muscle rehabilitation^8,62. The efficacy of these studies is difficult to assess, as their inclusion criteria do not always meet ISSM PE definitions; they include various types of treatments with either unreported or variable treatment duration^8,62. In addition, the number of men receiving treatment is small; the method of IELT measurement and follow-up is limited. Despite these reservations, behavioural therapy appears to improve IELT when compared with placebo in two out of four studies in a recent systematic review⁶². However, the picture is more mixed when behavioural therapy was compared with active drugs (that is, antidepressants); there was a trend towards improved IELT with active drugs or no significant differences^8,9,62. There is a need for more high-quality studies which are appropriately powered to demonstrate an effect using contemporary PE definitions. The combination of behavioural therapy with drug treatment (for example, DPX, chlorpromazine, paroxetine, and citalopram) has shown a significant but small improvement in outcome measures (that is, IELT) compared with the active drug alone in the three studies included in the systematic review⁶². The outcome measures included IELT in two studies and a validated questionnaire in one study. The improvement in IELT was 0.5–1 minute. Cormio et al. published the results of their well-designed open-label prospective randomised study in 2015⁶³. The inclusion criterion was based on the ISSM definition of PE. They compared outcomes of on-demand DPX with on-demand DPX plus behavioural therapy. Both groups had a significant improvement in IELT; however, the combination therapy resulted in a further 102- and 210-second increase at 12 and 24 weeks, respectively⁶³. In addition, 80% within the combination group no longer had PE at 24 weeks (versus zero in the DPX-alone group) based on the validated questionnaire PEDT.

Topical eutectic mixture for premature ejaculation

Topical local anaesthetic agents are the oldest treatments for PE. However, they are often criticised for not being specifically optimised for PE, for being slow-acting, and for requiring the use of condoms to prevent partner transference and resultant partner hypoanaesthesia^64,65. Topical eutectic mixture for PE (TEMPE, Plethora Solutions Ltd, Chalgrove, UK) was designed specifically for PE. It consists of 7.5 mg of lignocaine and 2.5 mg of prilocaine dissolved within a solution, which prevents penetration into the keratinised skin of the penile shaft⁶⁶. This results in a localised desensitising effect⁶⁶. The efficacy has been evaluated in two phase III placebo-controlled multicentre studies^64,66. In total, 530 men with mainly LPE according to the ISSM definition were randomly assigned to TEMPE or placebo in 69 centres across Europe and North America^64,66. A 6.3- and 4.6-fold increase in IELT was observed in both studies, respectively. There was also a significant improvement in the interprofessional education (IPE) domain scores in both studies^64,66. The odds of achieving an IELT of over 1 minute and over 2 minutes were 9 times and 12.8 times greater with TEMPE compared with placebo, respectively⁶⁶. However, although after 3 months 90% of men receiving TEMPE achieved a mean IELT of over 1 minute, 54% in the placebo group achieved the same⁶⁶. This suggests a very strong placebo effect, which again calls into question how much we truly understand about this condition and controversially whether it exists as a true medical condition.

Selective serotonin reuptake inhibitors

SSRIs inhibit axonal reuptake of serotonin from the synaptic cleft of central and peripheral serotonergic neurons by 5-HT transporters, resulting in enhanced 5-HT transmission and stimulation of post-synaptic membrane 5-HT_2c receptors¹⁹. SSRIs may be used daily or on demand. A recent meta-analysis evaluated long-acting (paroxetine, citalopram, fluoxetine, and fluvoxamine) and short-acting SSRIs⁶¹. Paroxetine was associated with the best efficacy, with an 11.6-fold increase in IELT in one study⁶¹. The use of an on-demand regime has been associated with less ejaculatory delay^67–70. Adverse effects are usually mild and include fatigue, yawning, nausea, and loose stools⁶¹. ED and libido reduction have also been reported, though less frequently compared with men using the drugs for depression^61,71. Men must be cautioned about SSRI withdrawal syndrome with abrupt drug cessation⁶¹.

DPX is currently the only SSRI marketed specifically and licenced for the treatment of PE. It has the largest efficacy and safety database, having been studied in over 6,000 men in a variety of well-conducted, placebo-controlled trials⁶⁴. A recent meta-analysis of PE treatments revealed that DPX is associated with a 3- to 4.3-fold increase in IELT over baseline in three large placebo-controlled trials^61,64. DPX has a good safety profile with side effects similar to those observed with other SSRIs^61,72. In a large open-label observational study comparing DPX with alternative treatments for PE (including other SSRIs, condoms, and behavioural therapy), DPX had a higher incidence of adverse events (12% versus 8.95%)⁷². The highest incidence of adverse events was observed in men over 65 using DPX and men 30–39 years old using other therapies⁷².

Despite the high efficacy of SSRIs and associated low rate of adverse events, the proportions of men who stopped using DPX were 79.1% within 6 months and 90.1% at 2 years⁷³. The commonest reasons for discontinuation were the following:

This suggests that more efficacious therapies are still required. Although similar complaints may be expressed by men with ED, ultimately the insertion of a penile prosthesis will allow a man to have sexual intercourse. Unfortunately, this is not the case with men with PE.

Phosphodiesterase-5 inhibitors

PDE5is are the gold-standard first treatment for men with ED. However, their role in PE remains unclear. PDE5 is expressed in the prostate, vas deferens, and seminal vesicles and may have a physiological role in ejaculation^74–76. The coexistence of ED and PE is common, occurring in up to 50% in some studies^77–80. In addition, 33.3% of men may confuse the two conditions⁸¹. This is not surprising. Men with ED require higher levels of arousal to attain an erection or may attempt to rush sexual intercourse prior to loss of their erection⁸⁰. Both of these situations will predispose them to a reduction in ejaculatory control and possible PE. Conversely, men with PE require a reduction in arousal to control ejaculation, which may worsen erectile function⁸⁰. Sexual dysfunction is also associated with performance anxiety, which may worsen erectile function^13,82.

Most studies appear to suggest that the use of PDE5is may be useful in the treatment of PE^83–85. However, they have been criticised for their poor methodology⁸². Two systematic reviews have failed to support the use of PDE5is in the treatment of PE except where PE coexists with ED^61,82.

Management options: novel agents

Conclusions

PE is a common problem with variability in definitions and efficacy measures of drugs used for this condition. The real importance for future drug development is the unification of definitions of PE and an agreed standard for what are acceptable measures and inclusion criteria in the trial setting. There remains uncertainty in assessing the true value of some of the drugs we already use in the management of this condition. There are different definitions for PE, different efficacy measures, and poor methodology in clinical trials. In addition, the high discontinuation rates suggest that our patients remain dissatisfied with the treatments we currently offer. Furthermore, one must be cautious to define a pathological condition often associated with a high placebo effect.

There are currently several novel agents which show promise for the future, but our optimism must be balanced against accepting suboptimal science and methodology in drug trials. PE continues to be the Cinderella of sexual medicine and requires funding and high-level research in both basic science and clinical trials. The oxytocin antagonists probably show the most future promise but data are still premature.