Ejaculation Threshold Hypothesis
In order to understand the suggested biological variation of the IELT in relation to the serotonergic system, delaying effects of SSRIs and suggested genetics, Waldinger and co-workers have proposed the existence of a threshold of the IELT (5,49).
In the case of a low setpoint of the threshold, men can only sustain a small amount of sexual arousal prior to ejaculation. Whatever these men do or fantasize during intercourse, any control of ejaculation remains marginal and these men ejaculate easily even when they are not fully aroused. The low threshold is assumed to be associated with a low 5-HT neurotransmission and probably a hypofunction of the 5-HT2C receptor and/or a hyperfunction of the 5-HT1A receptor, as mentioned earlier.
In the case of a higher setpoint, men will experience more control over their ejaculation time. They can sustain more sexual arousal before ejaculating. In these men, 5-HT neurotransmission varies around a normal or averaged level and the 5-HT2C receptor functions normally. The mean and range values of the setpoints that are considered to be normal or averaged are not known. These men have the neurobiological ability to voluntarily decide to get an ejaculation quickly or after a longer duration of intercourse.
In case of a high or very high setpoint, men may experience difficulty in ejaculating or cannot get an ejaculation even when fully sexually aroused. At a high setpoint, 5-HT neurotransmission is supposed to be increased, the 5-HT2C receptor sensitivity is enhanced, and/or the 5-HT1A receptor sensitivity is decreased.
According to this threshold hypothesis, it appears to be the level of 5-HT2C and 5-HT1A receptor activation that determines the setpoint and associated ejacu lation latency time of an individual man. In case of men with premature ejacula-tion or any man using serotonergic antidepressants, the SSRIs and clomipramine activate the 5-HT2C receptor and therefore switch the setpoint to a higher level leading to a delay in ejaculation. The effects of SSRIs on the setpoint appear to be individually determined; some men respond with extreme delay whereas others only experience a small delay at the same dose of the drug. Moreover, ces- sation of treatment results in a uniform reset of the setpoint within 3 – 5 days to the lower individually determined reference level, which is assumed genetically determined.
It is speculated that the threshold is mediated by serotonin neurotrans- mission and 5-HT receptors in the brainstem or spinal cord and may consist of serotonergic fibers that inhibit neurons that convey somatosensory information from the genitals. It is suggested that SSRIs enhance the inhibitory effects of these serotonergic neurons. However, also the cerebral cortex may mediate inhibitory impulses, but currently this has not been demonstrated. Apart from a suggested SSRI-induced increased inhibition of sensory input, the SSRIs might also delay ejaculation by interfering with spinal cord motoneurons of peripheral neurons that inhibit the internal genitals. Further studies are needed to unravel this important and intriguing question.
Course of Rapidity
It is generally believed that aging delays ejaculation. This assumption, might be true for men with a normal or average ejaculation time but has never been inves- tigated in men with premature ejaculation. In a stopwatch study (48) of 110 con- secutively enrolled men (aged 18 – 65 years) with lifelong premature ejaculation,
76% reported that throughout their lives, their speed of ejaculation had remained as rapid as at the first sexual contacts in puberty and adolescence, 23% reported that it had become even gradually faster with aging, and only 1% reported that it had become slower. From these data, it is questioned whether the fixed rapidity and even paradoxical shortening of the ejaculation latency time while getting older should be recognized as a part of the pathogenetic process of premature ejaculation. According to Waldinger, early ejaculation is thought of as a part of a normal biological variation of the IELT in men, but its paradoxical or fixed course through life is considered as being pathological. Chronic premature ejaculation appears to be the clinical syndrome of primary (lifelong) premature ejaculation. As yet, there is no real cure for lifelong premature ejaculation, though drugs may alleviate the symptoms, but only as long as they are being taken.
Premature Ejaculation and Genetics
In 1943, Schapiro noted that men with premature ejaculation seemed to have family members with similar complaints (19). Remarkably, this interesting observation has never been cited. To investigate the potential familial occurrence of premature ejaculation, I routinely asked 237 consecutively enrolled men with premature ejaculation about the family occurrence of similar complaints (23). Because of embarrassment only 14 men consented to ask male relatives about ejaculation latency. These 14 men reported a total of 11 first degree male relatives with information available for direct personal interview. In fact, 10 relatives fulfilled our strictly defined criterion of an ejaculation time of 1 min or less. In this small selected group of men, the calculated risk of having a first relative
with premature ejaculation was 91% (CI 59 – 99). Therefore, the odds of family occurrence are much higher than the suggested population prevalence rate of
4 – 39%. Moreover, the high odds ratio indicates a familiar occurrence of the syndrome, far higher than by chance alone. On the basis of this preliminary observation, the influence of genetics gains substantial credibility (23).
Drug Treatment for Premature Ejaculation
In 1943, Schapiro (19) described the use of topical anesthetic ointment to delay ejaculation. The use of anesthetics to diminish the sensitivity of the glans penis is probably the oldest form to treat premature ejaculation.
In 1973, the first report of successful ejaculation delay by clomipramine was published (51). However, in the 1970s and 1980s of the last century, drug treatment of premature ejaculation was not very popular. The introduction of the SSRIs meant a revolutionary change in the approach to and treatment of pre- mature ejaculation. SSRIs encompass five compounds (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) with a similar pharmacological mechan- ism of action. In 1994, Waldinger and colleagues published the first double-blind study on the ejaculation delaying effect of paroxetine (29). In last decade, all other SSRIs and clomipramine have repeatedly been investigated in their propensity to delay ejaculation (27 – 33,42 – 46,52 – 62). There is some evidence that fluvoxamine and citalopram have less effect in delaying ejaculation than paroxetine, sertraline, and fluoxetine (31,44).
Although the methodology of the initial drug treatment studies was rather poor, later double-blind and placebo-controlled studies replicated the genuine effect of clomipramine and SSRIs to delay ejaculation.
In spite of a development towards more evidence-based drug treatment research, the majority of studies still lack adequate design and methodology (15,40,41,48,50a). For the interpretation of drug treatment studies, it is important to bear in mind that the outcome values of the ejaculation time are dependent on both gender (e.g., assessment by the male or his female partner) and method (e.g., assessment by subjective reporting, questionnaire, or stopwatch) (15,40,41,48,50a). Recently, Waldinger and colleagues conducted a systematic review and meta-analysis of all drug treatment studies (41), performed between 1943 and 2003, demonstrating that single-blind and open-design studies and studies using subjective reporting or questionnaires all showed a higher variabi- lity in ejaculation delay than double-blind studies in which the ejaculation delay was prospectively assessed with a stopwatch. Of all 79 studies, only 11 studies (14.4%) (27,31,33,42 – 46,63 – 65) have been performed in accordance with the established criteria of evidence-based medicine (41).
Nevertheless, in spite of the inaccurate assessment of delay in most drug treatment studies, three drug treatment strategies to treat premature ejacula- tion can be distinguished: (1) daily treatment with serotonergic antidepressants, (2) as-needed treatment with antidepressants, and (3) as-needed treatment with anesthetic topical ointments.
Daily Treatment with Serotonergic Antidepressants
Daily treatment can be performed with paroxetine (20 – 40 mg), clomipramine (10 – 50 mg), sertraline (50 – 100 mg), and fluoxetine (20 – 40 mg). The recent meta-analysis of all drug treatment studies has demonstrated that paroxetine exerts the strongest ejaculation delay (41). Paroxetine, sertraline, and fluoxetine may give rise to side-effects like fatigue, yawning, mild nausea, loose stools, or perspiration. These side-effects often start in the first week after intake but gradu- ally disappear within 2 – 3 weeks. Ejaculation delay with daily treatment usually manifests itself at the end of the first or second week. With the exception of fluox- etine, it is advised not to stop the SSRIs acutely but gradually within 3 – 4 weeks, in order to avoid withdrawal symptoms, like dizziness and tremors. Side-effects of clomipramine may consist of nausea, dry mouth, and fatigue. Sometimes clo- mipramine and the SSRIs may give rise to reversible feelings of diminished libido or moderate decreased rigidity of the penis. It is advised that patients are told about all aforementioned side-effects when starting the treatment.
The impressive ejaculation delay by daily treatment with paroxetine and the other SSRIs can be explained by the neuropharmacological processes that occur during chronic SSRI administration to serotonergic neurons. After chronic SSRI administration and through desensitization of the 5-HT1A and 5-HT1B autoreceptors, 5-HT levels in the synaps have increased highly. The higher levels of 5-HT consequently activate the postsynaptic 5-HT2C and 5-HT1A receptors (1,2). Not only in humans, but also in male rats it has been found that chronic administration of fluoxetine (66) and paroxetine (67) signifi-cantly delays ejaculation latency. Remarkably, chronic administration of fluvox- amine exerts only a mild change in male rat ejaculatory behavior (49,67).
As-Needed Treatment with Antidepressants
Since 1993, only eight studies (28,68 – 74) on as-needed (on-demand) treatment have been published. Owing to this limited number of studies and to inadequate designs, a meta-analysis was insufficiently powered to provide final conclusions with regard to difference in efficacy and dose relationships (41). In spite of these scientific limitations, it has been found that clomipramine (10 – 50 mg) taken minimally 4 – 6 h prior to intercourse may be efficacious in delaying ejaculation. However, in contrast with the positive results of a single-blind on-demand study by McMahon and Touma (61) with 20 mg paroxetine, Waldinger et al. (75) have found in a double-blind study that on-demand use of 20 mg paroxetine has no or just minimal ejaculation delaying effects after 5 h in men with a premature ejaculation of ,1 min. It has to be noted that this lack of ejaculation delay after 5 h is in line with current knowledge of serotonin (5-HT) neurotransmission. After acute SSRI administration, there is no or only a mild increase of seroto- nergic neurotransmission in the synapse and no or only mild activation of postsynaptic 5-HT receptors. The lack of ejaculation delaying effects after acute paroxetine administration has also been found after acute treatment with SSRIs and clomipramine in male rats (76). Further well-controlled studies on acute SSRI treatment are needed to unravel the mean and range of the amount of ejaculation delay that can be accomplished with the on-demand strategy. However, it should be noted that due to pharmacodynamic limitations “on-demand” SSRI treatment, even with the new generation of SSRIs with a short half-life, will exert much less ejaculation delay than “daily” SSRI treatment (50b).
As-Needed Treatment with Anesthetic Topical Ointments
Only a few controlled studies have been performed with anesthetic ointments. In one study, the results of lidocaine – prilocaine cream 10 min before intercourse has been reported (77). In the Far East, there have been good results with SS cream according to evidence-based studies (41). SS cream is a locally produced cream consisting of various herbs, taken 1 – 2 h prior to intercourse (64,78 – 82).
Psychotherapy and Behavioral Therapy
Since the introduction of the SSRIs, the use of behavioral treatment has dimin- ished as first choice of treatment for “lifelong” premature ejaculation. However, by many sexologists psychotherapy and behavioral treatment, includ- ing the stop – start strategy of Semans and squeeze-technique of Masters and Johnson, are still advocated as the first choice of treatment for “secondary” premature ejaculation. However, I would again like to emphasize that the use of behavioral treatment for “secondary” premature ejaculation is also not based on well-controlled studies.
I have previously stated that psychotherapy is only indicated in men or couples who cannot accept premature ejaculation (5,83). In contrast to the classic psychological view, I have suggested that the purpose of psychodynamic or cognitive psychotherapy is not to learn how to delay ejaculation, but has to be how to cope with premature ejaculation, for example, in cases where medication has no or insufficient effect. The latter purpose of psychotherapy requires much more effort and real knowledge of psychotherapy from a sexologist than just giving instructions to a man on how to make love and to have intercourse.
Many people believe that retarded ejaculation is not a real problem for a couple, as they argue that retarded ejaculation enables a man to go on enough time to enable his female partner to be satisfied with one or even multiple orgasms. The reality of this syndrome is different. Many men suffer from delayed ejacula- tion and their female partners are very frustrated by it. Quite a number of women think they are not attractive to their partner and that he will be able to ejaculate when making love with another woman. Obviously, if coitus goes on too long, it may become painful for her. The failure to conceive is often a reason to seek help.
In DSM-IV (American Psychiatric Association, 1994), retarded ejaculation is termed Male Orgasmic Disorder and defined as “a persistent or recurrent delay in, or absence of, orgasm in a male following a normal sexual excitement phase during sexual activity that the clinician, taking into account the person’s age, judges to be adequate in focus, intensity, and duration.” In more simple terms, retarded ejaculation means that a man finds it difficult or impossible to ejaculate, despite the presence of adequate sexual stimulation, erection, and conscious desire to achieve orgasm. Some of these men may struggle to ejaculate with such des- peration that they may physically exhaust themselves, and sometimes even their partner, in the attempt. Delayed ejaculation may occur in coitus, masturbation (either by the patient or by the partner), as well as during anal or oral intercourse.
Throughout the years, a variety of terms have been used to refer to this eja- culatory disorder. Synonyms for delayed ejaculation are retarded ejaculation, inhibited ejaculation, difficult ejaculation, late ejaculation, and ejaculatio retarda or retardata. Other terms for failure of ejaculation are inability to ejacu- late, no ejaculation, anejaculation, ejaculatory incompetence, impotentia ejacu- landi or ejaculationis, ejaculatio deficiens or nulla, and lack (loss, failure, inability) of ejaculation.
It has to be noted that in DSM-IV there is no formal distinction between retarded ejaculation and failure of ejaculation. Both entities are erroneously termed male orgasmic disorder.
One distinguishes a lifelong (primary) and acquired (secondary) form. If the disorder has always been present, the disorder is termed as lifelong. In the acquired form, the disorder appears somewhere in life after previous normal ejaculatory functioning.
If ejaculation is delayed in all situations, in all sexual activities and with all partners, the disorder is “generalized.” In contrast, the disorder is “situational” if the delayed ejaculation is limited to certain situations or with certain partners. Situational delayed ejaculation may therefore give rise to different clinical presentations: A man is unable to ejaculate intravaginally but can do so by mas- turbation, a man is able to ejaculate during sex with a man but not with a woman, a man is able to ejaculate with one woman but not another, a man is able to ejaculate with the same woman on one occasion but not the next, or a man can only ejaculate when the sexual act is accompanied by specific stimulation.
In contrast with premature ejaculation, lifelong delayed ejaculation is a relatively uncommon condition in clinical practice. In many studies on the distribution of diagnosis of sexual dysfunctions in males, delayed ejaculation is often among the least presented sexual disorders. The prevalence in the general population is also rather low. Regarding lifelong delayed ejaculation, Nathan (84) found a prevalence of 1.5 in 1000. Acquired delayed ejaculation has little higher preva- lence of 3 – 4% in men below the age of 65.
Lifelong Delayed Ejaculation
According to the classical psychological view, lifelong delayed ejaculation is attributed to fear, anxiety, hostility, and relationship difficulties (85 – 87). Many different manifestations of anxiety and fear have been hypothesized, including fears of death and castration, fear of loss of self resulting from loss of semen, fear of castration by the female genitals, fear that ejaculation would hurt the female, fear of being hurt by the female, performance anxiety, unwillingness to give of oneself as an expression of love, fear of impregnating the female, and guilt secondary to a strict religious upbringing.
The psychological ideas and explanations may have face validity in some individual cases, but there are no well-controlled studies that support a general- ization of any of the various psychological hypotheses. The psychological, cultural, and religious factors that may lead to lifelong delayed ejaculation clearly requires further investigations.
Waldinger (1,5) postulates that lifelong delayed ejaculation is part of the biologi- cal variability of the IELT in men. According to this view, there is a variability in the extent of delayed ejaculation, from mildly delayed to severely delayed and lastly a failure of ejaculation. I suggest that this biological variability is related to genetic factors. In case this is true, it means that men may be born with a bio- logical vulnerability to develop delayed ejaculation. Whether environmental factors affect the neurobiological vulnerability remains to be understood.
From animal and human studies, it is known that in particular it is the ser- otonergic system which is involved in ejaculation. On the basis of animal studies, I suggest that lifelong delayed ejaculation is related to a hyperfunction of the 5-HT2C receptor and/or a hypofunction of the 5-HT1A receptor. Whether dopa- mine and oxytocine play a role in lifelong delayed ejaculation remains to be elucidated.
Unfortunately there is no drug treatment available for delayed ejaculation in men. In animals, the 5-HT1A receptor agonist, 8-OH-DPAT, fastens the ejacu- lation latency, but such selective 5-HT1A agonists are not yet available for safe human use. Another possibility is a selective blockade of the 5-HT2C receptor. However, in a stopwatch controlled study in men with premature ejaculation, the 5-HT2C receptor blocking antidepressants, nefazodone and mirtazapine, did not lead to either delayed ejaculation or a faster ejaculation time.
Treatment of Lifelong Delayed Ejaculation
With every man presenting with delayed ejaculation, it is essential to obtain a full sexual and medical history and clinical examination of the patient. It is important to find out the situations in which ejaculation is impaired (location, sexual activity, specific partner), the frequency with which ejaculation is inhibited, the degree of delay of orgasm, whether the complaint existed from the first sexual encounters (lifelong) or occurred later in life (acquired), and whether orgasm and ejaculation are both lacking.
Various treatments have been used to treat men with delayed ejaculation: Vibratory and electrical stimulation, a variety of sexual exercises, and a range of psychotherapeutic techniques (88 – 91). These treatments have been used sep- arately or in combination with one or more others. Research on the effectiveness of these treatments is limited to uncontrolled studies on individual patients or short series of patients (92). Controlled studies are not available.
By vibratory stimulation (93) of the penis an ejaculation can be induced. The percentage of success to cure lifelong delayed ejaculation, however, is unknown. Electrical stimulation (94) of the internal ejaculatory organs by a transrectal electrical probe (electro-ejaculation) is mainly used to obtain semen in paraplegic men. This intervention is extremely painful in men with normal sensation and is not an option to treat lifelong delayed ejaculation. Masturbation exercises have been extensively used in the treatment of delayed ejaculation. Kaplan (85) describes a method in which a period of undemanding sensate focus exercises is followed by a period in which a man masturbates, initially alone and subsequently in circumstances in which he becomes gradually closer to his female partner. Once the patient has had an orgasm in the presence of his partner, he masturbates in a number of steps in which the penis is closer to the vagina during masturbation. Finally, he enters the vagina and combined coital and manual stimulation is then used to induce ejaculation. Apart from mas- turbation exercises, individual psychodynamic psychotherapy, marital therapy, rational emotive therapy, and social skills training have been used to treat delayed ejaculation. Because controlled studies are not available, it is very diffi- cult to evaluate the results. The overall impression of these different approaches is that some patients are actually cured after treatment although most patients are only somewhat improved or unchanged. In the absence of comparative studies, it is not possible to compare the effectiveness of different treatments. A major methodological impairment is that in most studies, outcome is assessed by means of a single statement (“improved,” “cured,” or “unchanged”), more specific information on ejaculation is lacking, and that treatment has not been standardized in most studies. Because of these methodological deficiencies, no firm conclusion or recommendation on the optimal treatment approach can be given (92). Currently, the best way to treat men with lifelong delayed ejaculation is to inform patients beforehand that success of psychotherapy cannot be guaranteed, but that it may be worth trying, as effective drug treatment is not yet available. At present, a combination of masturbation exercises and general therapeutic interventions may have a chance for success.
In spite of the above-mentioned treatment options, it is generally believed that lifelong retarded ejaculation is difficult to treat. In my opinion, continuous psychological, cultural of religious factors prohibiting sexual feelings may perhaps lead to a release of stress hormones that might disturb the full develop- ment of or even damage cerebral areas and neuronal pathways that are important for the ejaculation process. This might be one of the reasons that although psychological factors may heavily contribute to retarded ejaculation, psychother- apy alone is often hardly effective. Further research of lifelong retarded ejacula- tion is of utmost importance to unravel the neurobiology and interaction with psychological factors of this distressing ejaculatory disorder.