Male Ejaculation and Orgasmic Disorders
Ejaculation and orgasm usually occur simultaneously in men even though ejaculation and orgasm are two separate phenomenona. Ejaculation occurs in the genital organs, whereas orgasmic sensations, being related to the genitals, are mainly a cerebral event which involves the whole body. In a few clinical syndromes, orgasm or ejaculation appears to exist independent of each other. For example, men with anesthetic ejaculation experience a normal ejaculation, but suffer from an absence of orgasmic sensation. On the other hand, men with premature ejaculation suffer from a disturbed speed of ejaculation, but do have intact orgasmic sensation.
It is very unfortunate that a clear distinction between orgasm and ejacula- tion has not been made in DSM-IV (American Psychiatric Association, 1994). In DSM-IV, ejaculation disorders are categorized under the heading of Orgasmic Disorders. Strangely, in DSM-IV retarded ejaculation has been called “male orgasmic disorder,” analogous to “female orgasmic disorder,” whereas premature ejaculation has not been called premature orgasm. Moreover, two rather rare syndromes, anesthetic ejaculation as well as partial ejaculatory incompetence, have not been mentioned at all in DSM-IV.
The synonymous terminology of ejaculation and orgasm in DSM-IV is not in line with current neurobiological thinking. In recent years, much has become known about the neurobiology and neuropharmacology of ejaculation. From a neurobiological perspective, it seems likely that orgasm and ejaculation are mediated by different neural circuits and various neurotransmitter systems.
In last century, ejaculatory disorders have been approached mainly from a psychological perspective. Although neuroscientists over the last 30 years have gained clear evidence of the important role of the central nervous system in ejaculation, it is only in the last decade that clinicians have begun to accept that ejaculatory disturbances are neurobiologically determined and can be treated by medication. However, in contrast with what is known about ejaculation, there is still limited information about the neurobiology of orgasm.
The history of ejaculatory and orgasm disturbances is colored with much speculations and particularly with a dramatic absence of evidence-based research. For example, many sexologists still believe in or favor one of the many psychological etiologies that have been put forward for the different ejacu- latory disturbances. However, not one of these psychological hypotheses and associated treatments has been thoroughly investigated according to evidence- based medical principles. Most of these studies are characterized by very weak methodologies and designs.
I myself am convinced that evidence-based medical research is the only way to understand and investigate the efficacy of both drug- and psychological treatment of ejaculatory disturbances. Thus, I have written this chapter with a focus on methodology and design. Today, a clinical understanding of male eja- culatory and orgasm disturbances is no longer possible without a basic under- standing of the neurophysiology, neuropharmacology, and neuroanatomy of serotonergic neurons in the brain. Therefore, I will start off by giving you a general explanation and overview of serotonergic neurotransmission, serotoner- gic receptors and how animal sexual behavior determines our understanding of sexual psychopharmacology. After this basic pharmacological introduction, I will describe the ejaculatory disturbances in rank order of frequency in the general population. As most research in recent years has been focused on prema- ture ejaculation, it is inevitable that this disorder receives more attention than the other ejaculatory disorders.
The mechanism of ejaculation is conveniently divided into two phases, emission and expulsion.
Emission: During the emission phase, semen (e.g., sperm and seminal fluids) is deposited into the posterior urethra through contractions of the smooth muscles of the vasa deferentia, seminal vesicles, and prostate. At the same time, the internal sphincter of the urinary bladder is closed, thereby prevent- ing retrograde passage of the semen into the bladder. The closure of the sphincter also prevents urine from mixing with the semen. Emission and bladder neck closure are mediated through the thoracolumbar sympathetic system. It is suggested that the sensation of ejaculatory inevitability parallels the emission phase.
Expulsion (or true ejaculation): Emission is immediately followed by expulsion. During expulsion, the semen is forcefully propelled along the urethra and out of the penis by clonic contractions of the striated bulbar muscles of the urethra and contractions of the striated muscles of the pelvic floor (mainly bulbospongiosus muscles).
Expulsion is mediated by the somatic nervous system. Orgasm is associated in timing with the expulsive phase.
There is limited knowledge about the physiological mechanisms and neurobiol- ogy underlying the sensation of orgasm. Orgasm is a complex response involving the whole body. During orgasm, there are changes in the genitalia, in skeletal muscle tone (characteristic spastic contractions of the feet), contractions of facial musculature, vocal reactions (moaning or sighing), semivoluntary move- ments, general cardiovascular (elevated systolic and diastolic blood pressure) and respiratory changes, somatic sensory experiences, and an altered consciousness.
The intense feelings of pleasure and desire accompanying orgasm are mediated by the brain.
NEUROBIOLOGY OF EJACULATION
Serotonin, 5-Hydroxytryptamine Neurotransmission and 5-HT Receptors
For a better understanding of the neurobiology of premature and delayed ejacula- tion and its treatments, it is a prerequisite to have some basic knowledge of what is happening in serotonergic neurons in the central nervous system (1,2).
Serotonergic neurons originate in the raphe nuclei and adjacent reticular formation in the brainstem. There is a clear dichotomy in the serotonergic (5-hydroxytryptamine, 5-HT) system neuronal cell groups (1). A rostral part with cell-bodies in the midbrain and rostral pons projecting to the forebrain and a caudal part with cell-bodies predominantly in the medulla oblongata with projections to the spinal cord. In the forebrain and spinal cord, the serotoner- gic neurons contact other serotonergic neurons. The location of connection is the synaps, in which the neurotransmitter serotonin provides information from one neuron to another. After its fabrication in the cell-body, serotonin runs through the serotonergic neuron to the presynaptic membrane, through which it is released into the synaps. In the synaps, serotonin proceeds to receptors at the opposite neuron (postsynaptic receptors) and after it has contacted these receptors serotonin runs back to the presynaptic membrane. Through the activity of sero- tonin transporters (5-HTT) in the presynaptic membrane, serotonin is brought back into the presynaptic neuron. The process of serotonin release and its action on postsynaptic receptors is called serotonergic neurotransmission.
There is normally a sort of equilibrium in the serotonergic neurotrans-mission system due to remarkable mechanisms. If too much serotonin is released from the presynaptic neuron into the synaps, the so-called 5-HT1B autoreceptors, located in the presynaptic membrane, become activated. Their activation results in a diminished release of serotonin in the synaps. Consequently, the equilibrium is restored. This feedback mechanism of the cell, where the released 5-HT inhibits its own release, is a frequently occurring principle in neurotransmitter regulation and can allow the system with the possibility to prevent overstimula- tion of postsynaptic receptors (1).
However, serotonergic neurotransmission becomes seriously disturbed by the action of serotonergic antidepressants. Selective serotonin reuptake inhibi- tors (SSRIs) block the 5-HT transporters, both in the presynaptic membrane and around the cell-body. As a consequence, serotonin concentration increases outside the cell-body and in the synapses. Owing to the increased serotonin levels, 5-HT1A autoreceptors at the surface of the cell-body and 5-HT1B auto- receptors in the presynaptic membrane become activated. The activation of both the somatodendritic 5-HT1A autoreceptors and the presynaptic 5-HT1B auto- receptors results in an inhibition of 5-HT release into the synaptic cleft. Conse- quently, serotonin concentration in the synaps diminishes but remains slightly increased due to blockage of the 5-HT transporters leading to some stimulation of all postsynaptic 5-HT receptors. After some days, the 5-HT1A and 5-HT1B autoreceptors become desensitized resulting in a diminished inhibitory action of these receptors to 5-HT release. Consequently, serotonin again becomes released into the synaps. However, due to the SSRI-induced continuous blockade of the 5-HT transporters, serotonin cannot get back into the presynaptic neuron, and as a consequence serotonin levels in the synaps become higher. This increased serotoneric neurotransmission exerts a stronger effect on all post- synaptic receptors. It is the action of those postsynaptic receptors that determines the clinical effects of the SSRIs.
Male Rat Sexual Behavior
Male rat studies have demonstrated that serotonin (5-HT) and 5-HT receptors are involved in the ejaculatory process. As far as is currently known, 5-HT2C and 5-HT1A receptors determine the speed of ejaculation. For example, studies with D-lysergic acid diethylamide and quipazine, which are nonselective 5-HT2C agonists, suggest that stimulating 5-HT2C receptors delays ejaculation (3). However, 2,5-dimethoxy-4-iodophenyl-2-aminopropane, which equally stimulates 5-HT2A and 5-HT2C receptors, also increases ejaculation latency (4), whereas the selective 5-HT2A receptor agonist 2,5-dimethoxy 4-methylampheta- mine does not have this effect (3). On the other hand, activation of postsynaptic 5-HT1A receptors by the selective 5-HT1A receptor agonist 8-hydroxy-2- (di-n-propylaminotetralin) in male rats resulted in shorter ejaculation latency (3).
On the basis of these male rat studies, Waldinger (1,5) has hypothesized that premature ejaculation is related to a hypofunction of the 5-HT2C receptor and/or a hyperfunction of the 5-HT1A receptor. In contrast, delayed ejaculation is postulated to be related to a hyperfunction of the 5-HT2C receptor and/or a hypofunction of the 5-HT1A receptor.
In recent years, much progress has been made in neuroanatomical research of eja- culatory processes. Most knowledge about the functional neuroanatomy of ejacu- lation is derived from male rat studies. With regard to male rat copulatory behavior, one has to distinguish among brain, brainstem, and spinal cord regions that become activated before and following ejaculation, when sensory infor- mation returns from the genitals (Fig. 9.1). The medial preoptic area (MPOA) in the rostral hypothalamus and the nucleus paragigantocellularis (nPGi) in the ventral medulla (6,7) are suggested as being important players in the process leading towards ejaculation. Electrical stimulation of the MPOA promotes ejacu- lation (8). It is hypothesized that ejaculation is tonically inhibited by serotonergic pathways descending from the nPGi to the lumbosacral motor nuclei. The present hypothesis is that the nPGi itself is inhibited by inhibitory stimuli from the MPOA. Disinhibition of the nPGi is supposed to lead to an ejaculation. The dis- covery of serotonergic neurons in the nPGi and the well-known ejaculation delay induced by serotonergic antidepressants suggests an action of the SSRIs on the nPGi. However, the precise location in the CNS on which SSRIs act to inhibit ejaculation has not yet been demonstrated.
On the other hand, brain areas activated as a result of the occurrence of one or more ejaculations have been observed in several mammals (9). Using expression of the immediate early gene, c-fos, as a marker for neural activity
in male rats, Coolen and co-workers (9 – 13) demonstrated the presence of distinct ejaculation-related neural activation in several brain regions following ejacula- tion: the posteromedial part of the bed nucleus of the stria terminalis (BNSTpm), a lateral subarea in the posterodorsal part of the medial amygdala (MEApd), the posterodorsal preoptic nucleus (PD), and the medial part of the parvicellular subparafascicular nucleus (SPFp) of the thalamus. These brain regions containing ejaculation-induced activation are extensively interconnected and reciprocally connected with the MPOA (12), forming an ejaculation-related subcircuit within the larger brain circuits underlying male sexual behavior (12). The func- tional significance of this ejaculation-subcircuit is still poorly understood but it might well be that these areas play a role in “satiety” and thus mediate the post- ejaculatory interval.
Truitt and Coolen (13) highlighted the role of the lumbar spinal cord in the processing of ejaculation. They identified a group of lumbar spinothalamic cells (LSt) that are specifically activated after ejaculation, and provide direct genital sensory inputs to the SPFp in the thalamus and the ejaculation-related subcircuit in the brain. The LSt cells also project to sympathetic and parasympathetic neurons related to the genitals. It is suggested that the LSt cells contribute to trig- gering the ejaculatory reflex and the sensation of ejaculation, that is, orgasm. These and other animal studies have clearly shown the existence of a neural circuitry for ejaculation in mammals.
Positron Emission Tomography-Scan Studies in Humans
Although male rat studies are of utmost importance for a better understanding of the neurobiology of ejaculation, brain imaging studies in humans are the tools which provide a better understanding of how the human brain mediates ejacula- tion and orgasm. Brain imaging studies will probably lead to a deeper insight into which parts of the brain mediate ejaculation and which parts are involved in the mechanism of orgasm, how these neural areas are linked to each other, and which parts are disturbed in the different ejaculatory and orgasm disturbances. The first Positron Emission Tomography (PET)-scan study during ejaculation has recently been conducted by Holstege et al. (14). Eleven healthy male volunteers were brought to ejaculation by manual stimulation of their female partner. The PET technique using radioactive water (H2 O) shows increases or decreases in blood flow in distinct parts of the brain, representing increases or decreases of activation of neurons in these areas. It was found that during ejaculation the stron- gest activation occurred in the so-called mesodiencephalic region, a brain area which comprises structures as the ventral tegmental area (VTA), also known as the “reward are” and the lateral central tegmental field. This area comprises dopa- minergic neurons. The activation of the VTA shows that ejaculation leads to rewarding processes in the brain. Increased activation was also observed in the lateral putamen and adjoining parts of the claustrum and insula, and certain parts of the prefrontal, temporal, parietal, and insular cortexes. The meaning of
all the activations of these various cortical areas is not yet clear. Further studies need to clarify whether associated sensations of orgasm are mediated by these cortical areas. Unexpectedly, a very strong activation was found in parts of the cerebellum, the meaning of it remaining unclear. Decreased blood flow, and thus less activity was found in the amygdala during sexual arousal, erection, and ejaculation. This may perhaps indicate that the brain looses a state of anxiety or fear during sexual activity. Hypothalamic involvement, as has been demonstrated in animal sexual behavior, has not been found in these male volun- teers. Obviously, further PET-scan studies are needed to unravel this human and animal dichotomy.
Premature ejaculation (ejaculatio praecox, rapid ejaculation, or early ejaculation) is the most frequent male ejaculatory disturbance. During the last century, prema- ture ejaculation has been considered from both a medical and a psychological view, often resulting in contrasting psychotherapeutic and drug treatment approaches. For a better understanding of the current debate regarding its etiol- ogy and treatment, it is important to consider the history of how clinicians thought about and treated premature ejaculation.
Waldinger (5,15) distinguishes four periods in the approach to and treatment of premature ejaculation.
The First Period (1887 – 1917): Early Ejaculation
In 1887, Gross (16) described the first case of early ejaculation in medical litera- ture. A second report of von Krafft-Ebing (17) followed in 1901. Although publications were rare, it is worth noting that during the first 30 years of its existence in the medical literature, early ejaculation was viewed as an abnormal phenomenon but not significantly as a psychological disturbance.
The Second Period (1917 – 1950): Neurosis and
In 1917, Abraham (18) described early ejaculation as ejaculatio praecox and stated that it was a symptom of a neurosis caused by unconscious conflicts. Treat- ment should consist of classic psychoanalysis. On the other hand, some phys- icians stated that premature ejaculation was due to anatomical urological abnormalities, such as a too short foreskin frenulum or changes in the posterior urethra, which had to be treated with incision of the foreskin or electrocautery of the verumontanum. In 1943, Schapiro (19) argued that premature ejaculation was neither a pure psychological nor a pure somatic disorder, but a psycho- somatic disturbance caused by a combination of a psychologically overanxious constitution and a weak ejaculatory system. Schapiro described two types of premature ejaculation, type B in which early ejaculation existed from the first intercourses and type A, which led to erectile dysfunction. Many years later, both types became distinguished as the primary (lifelong) and secondary (acquired) forms of premature ejaculation (20).
The Third Period (1950 – 1990): Learned Behavior
The biological component of premature ejaculation and therefore also drug treat- ment, advocated by Schapiro, was ignored by the majority of sexologists who advocated psychoanalytic treatment. This neglect became even more pronounced after Masters and Johnson (21) claimed the high success rates of behavioral therapy in the form of the squeeze technique, an adaptation of the stop – start tech- nique published by Semans (22) in 1956. Masters and Johnson stated that men with premature ejaculation had learned this rapidity behavior as a result of their rushed initial experiences of sexual intercourse.
The Fourth Period (1990 to Present): Neurobiology and Genetics
Since the 1990s, there has been an increasing number of publications on the efficacy of SSRIs, clomipramine, and topical anesthetic creams in delaying ejaculation. At the same time, in 1998, Waldinger (1) postulated a new neuro- biological view arguing that premature ejaculation is related to disturbance of serotonin (5-HT) receptors in specific areas of the central nervous system with a possible genetic vulnerability (5,23).
Premature ejaculation is often cited as being the most common male sexual dys- function. The exact prevalence, however, is unknown as this appeared difficult to determine. Although it has been estimated that as many as 36% of all men in the general population experience premature ejaculation (24), other estimates have been lower. For example, Gebhard and Johnson (25), from a reanalysis of the Kinsey data, determined that 4% of the men interviewed reported ejaculating within 1 min of intromission. The large differences in prevalence numbers are mainly due to the use of various and often totally different definitions of prema- ture ejaculation that have been used. Only by the general use of an empirically defined definition and identical tools to measure the ejaculation time, methodo- logically correct epidemiological studies can provide reliable prevalence data. Such studies have not been performed yet.
Evidence-based medicine means that the formulation of a seemingly attractive hypothesis of the cause of a disease is not enough for scientific acceptance. There needs to be empirical evidence, preferably replicated in various controlled studies.
For many decades, premature ejaculation was considered to be a psycho- logical disorder that had to be treated with psychotherapy. However, psychologi- cal treatments and underlying theories mostly relied on case reports, series of case report studies, and opinions of some leading psychotherapists and sexo- logists. They were not based on controlled studies. I believe this to be a typical example of authority- or opinion-based medicine (15).
In contrast to authority-based medicine, evidence-based medicine (26) has been accepted today as the hallmark for clinical research and medical practice. Particularly in last decade, randomized clinical trials with clomipramine (27,28) and some SSRIs (29 – 33) have repeatedly demonstrated the efficacy of serotonergic antidepressants to delay ejaculation. In spite of these studies, the belief persists among those involved in sexology that premature ejaculation is a psychological disorder. In order to unravel this dichotomy, it is important to apply principles of evidence-based medicine to both the psychological and neurobiological approaches to premature ejaculation and its treatments.
Evidence-Based Research: Psychotherapy
The psychoanalytic idea of unconscious conflicts being the cause of premature ejaculation has never been investigated in a manner that allowed generalization, as only case reports on psychoanalytic therapy have been published.
But this is also true for behavioural therapy. Masters and Johnson (21) deliberately refuted a definition of premature ejaculation in terms of a man’s eja- culation time duration. Instead, they insisted on defining premature ejaculation in terms of the female partner response, for example, as a male’s inability to inhibit ejaculation long enough for the partner to reach orgasm in 50% of intercourses. It is obvious that their definition is inadequate because it implies that any male partner of females who have difficulty in reaching orgasm on 50% of intercourses suffers from premature ejaculation.
Masters and Johnson argued that premature ejaculation was conditioned by experiencing first sexual contacts in a rapid way (e.g., in the back seat of a car or with an impatient prostitute). However, Masters and Johnson, and sexologists who followed their ideas, have never provided any evidence-based data for this assumption. Regarding their proposed behavioral squeeze technique treat- ment, Masters and Johnson claimed a 97% success for delaying ejaculation. However, this very high percentage of success has never been replicated by others.
Usually, a lack of reproducible data leads to critical comments. This is one of the basic principles of evidence-based medicine. The effects of a treatment intervention should be reproducible by others. However, critical comments were not appreciated in the traditional sexological thinking of the late 20th century. This nonscientifically supported and uncritical belief in behavioral treat- ment still exists today, in spite of clear evidence-based medical research in favor of the neurobiological view. But the criticism is justified. The methodological insufficiencies of the report of Masters and Johnson are very serious. Their report on the efficacy of the squeeze method contains numerous biases.
First, there was a bias in selection and allocation of the subjects, the patients were not randomized to the new squeeze technique, or the older stop – start technique, or a nonsense behavioral technique. Second, the treatment design was open and not double-blinded. Further, the diagnosis of premature eja- culation was not quantified and therefore inaccurate, particularly since Masters and Johnson used an obscure definition of premature ejaculation. Baseline data were not reported, and inclusion and exclusion criteria were lacking. The assess- ment of success was subjectively reported without quantification or scoring scales. In addition, Masters and Johnson did not provide any information on their data processing. In spite of all these methodological flaws, their behavioral technique has received worldwide uncritical acceptance and been promoted as the best method of treatment. Even the very poor results of two studies (34,35) on behavioral therapy (also poorly designed) could not prevent sexologists from continuing to claim the squeeze technique as the best method of treatment. Not only the squeeze technique, but also all sorts of psychotherapy, including thought stopping, Gestalt therapy, transactional analysis, group therapy, and bibliotherapy, have been proposed as being effective (36 – 39). Also the efficacy of these psychotherapies has only been suggested in case reports and were never investigated in well-designed controlled studies.
In my opinion, the uncritical acceptance of the squeeze technique as first choice treatment is a clear example of the influence of opinion- or authority- based medicine, as in those years Masters and Johnson were famous for their new approaches in the treatment of sexual disorders (15). It did not seem to be an issue then that Masters and Johnson—these so highly esteemed sexolo- gists—did not produce any evidence-based data for their claimed discovery.
Evidence-Based Research: Drug Treatment
In contrast with the easily accepted behavioral treatment by sexologists, drug treatment had to prove itself far more explicitly to avoid rejection by pro- fessionals in the field. Only a few physicians have tried to develop drug strategies to treat premature ejaculation. Currently, in spite of some residual ambiguous attitudes of many sexologists, drug treatment with serotonergic antidepressants are accepted as effective therapy. Despite of all circumstantial evidence, it should be emphasized that a scientific approach to investigating empirical evi- dence remains obligatory (40). To investigate how far differences in method- ology may be of influence on clinical outcome of drug treatment studies, Waldinger and co-workers conducted an systematic review and meta-analysis of all drug treatment studies that were published between 1943 and 2003 (41).
In this study, several methodological evidence-based criteria were com-pared such as study design (single-blind and open-design vs. double-blind), tools for diagnostic testing (stopwatch vs. subjective reporting or questionnaire) and means of assessment (prospective vs. retrospective). The results revealed that from 79 publications on drug treatment, 35 studies involved serotonergic antidepressants. It was clearly demonstrated that both single-blind and open- design studies as well as studies using a questionnaire or subjective report on the ejaculation time led to a higher variability, that means exaggerated responses, in ejaculatory delay. Only eight studies (27,31,33,42 – 46) (18.5%) fulfilled all criteria of evidence-based medicine, for example, double-blind studies prospec- tively using real time stopwatch assessments at each intercourse both at baseline and during the drug trial. Regarding daily treatment, a similar efficacy for parox- etine, clomipramine, sertraline, and fluoxetine has been demonstrated, whereas the efficacy of paroxetine was found to be clearly stronger than all aforemen- tioned drugs.
Operational Definition of Premature Ejaculation
For evidence-based research, it is of utmost importance to have a definition of premature ejaculation. However, because of conflicting ideas about the essence of premature ejaculation, sexologists have never reached an agreement on a definition.
DSM-IV (47) defines premature ejaculation as “persistent or recurrent eja-culation with minimal sexual stimulation before, upon, or shortly after penetration and before the person wishes it.” Until recently, any scientific basis for the DSM-IV definition was lacking. For instance, the meaning of “persistent,” “recur- rent,” “minimal,” and “shortly after” is vague and certainly needs further qualification. In order to get an empirically operationalized definition, Waldinger and co-workers investigated 110 consecutively enrolled men with lifelong prema- ture ejaculation (48). In this study, men and their female partners were instructed to use a stopwatch at home during each coitus for a period of 4 weeks (Fig. 9.2). It was found that 10% of these men ejaculated between 1 and 2 min but that the majority (90%) of them ejaculated within 1 min of intromission, and even 80% actually ejaculating within 30 s whereas 60% ejaculated within 15 s (48). The age of the men and duration of their relationship were not correlated with the eja- culation time. On the basis of this study, Waldinger and co-workers empirically defined lifelong premature ejaculation as an ejaculation that is ,1 min in .90% of episodes of sexual intercourse, independent of age and duration of relationship (48). It has to be noted that this definition defines premature ejacula- tion as being an early ejaculation that is independent of psychological or relation- ship distress. Thus, assessment by stopwatch revealed that premature ejaculation is a matter of seconds and not of minutes. In this respect, the ICD-10 definition (e.g., ejaculation before or within 15 s) seems more appropriate than the DSM-IV definition, but both need to be adapted to these recent data.
The “Ejaculation Distribution Theory” of Premature Ejaculation
Waldinger (5,49) formulated a new theory on the etiology and genesis of lifelong premature ejaculation. He postulated that lifelong premature ejaculation is not an
Figure 9.2 The IELT (29) measured by stopwatch in a sample of 110 Dutch males with lifelong premature ejaculation. Ninety percent ejaculates within 1 min and 80% ejaculates within 30 s (48).
acquired disorder due to habituation of initial hurried intercourses, as has been suggested by Masters and Johnson. Instead, Waldinger argues that early ejacula- tion is part of a normal biological variability of the intravaginal ejaculation latency time (IELT) in men, with a possible familial genetic vulnerability (5,23,49). In 1994, Waldinger et al., introduced and defined the IELT as a measure for pharmacological research (29). The IELT is the time between vagi- nal penetration and intravaginal ejaculation (29,31). According to Waldinger, early ejaculation is primarily a neurobiological phenomenon, which may or may not secondarily lead to psychological or psychosocial distress. Dependent on intra- and interpersonal and probably also cultural factors, early ejaculation may become perceived as premature ejaculation. Both animal and large-scale human epidemiological stopwatch studies are needed to demonstrate the exist- ence of a biological continuum of the IELT.
On the basis of animal and human psychopharmacological studies, Waldinger and co-workers further postulated that lifelong premature ejaculation is related to decreased central serotonergic neurotransmission, and 5-HT2C receptor hyposensitivity and/or 5-HT1A receptor hypersensitivity (1,5,49,50a). Treatment should therefore consist of 5-HT2C receptor stimulation and/or
5-HT1A receptor inhibition.
Evidence for the role of the 5-HT2C receptor has been found in four stopwatch studies in men with premature ejaculation (31,42 – 44). It was demonstrated that the 5-HT2C receptor stimulating and the 5-HT2C blocking antidepressants exerted an ejaculation delay and absence of ejaculation delay, respectively. In a double-blind placebo-controlled study with the 5-HT2C/5-HT2A receptor antagonist and 5-HT/noradrenaline reuptake inhibitor nefazo-done, 400 mg nefazodone daily did not exert any ejaculation delay in contrast to a significant delay after 20 mg paroxetine daily and 50 mg sertraline daily (42). In a similar study, the 5-HT2C/5-HT3 receptor antagonist, and noradrenergic and specific serotonergic antidepressant mirtazapine did not induce ejaculation delay compared with the significant delay resulting from 20 mg paroxetine daily (43). In both studies, nefazodone and mirtazapine did not delay ejaculation. Recent research suggests that 5-HT1A receptors are likely to play a more important role than 5-HT2C receptors in premature ejaculation and its treatment (50b). Further studies with selective 5-HT2C and 5-HT1A agonist and antagonists are encouraged to elucidate still undiscovered pharmacological mechanisms under- lying the ejaculatory process.