In 1998, Waldinger et al. [10] postulated that the variability of the IELT is caused by neurobiological and genetic factors, e.g., that the persistently short IELTs in men with lifelong PE are associated with diminished serotonin (5-hydroxytryptamine, or 5-HT) neurotransmission, a hypersensitivity of 5-HT_1A receptors, and/or a hypofunction of 5-HT_2C receptors. Notably, due to an absence of selective 5-HT_1A and 5-HT_2C receptor ligands for safe human usage, this hypothesis has sofar not been confirmed.

It should be noted that a characteristic feature of lifelong PE is the inability of a man to control the duration of his IELTs. Whatever the man would do, whatever techniques applied, whatever he thinks, or feels, his IELT is nearly always a matter of seconds, without much variation. However, usually these men mention that an IELT is sometimes longer than usual for unknown reasons. Actually, the affected man with lifelong PE is victim of his own very short IELTs and he is not able to change it. Men with lifelong PE have a rigid pattern of very short IELTs, without having the capability to change this rigidity. What causes this rigid pattern of short IELTs? The answer to this question is related to central neurobiological mechanisms and may also be related to genetic aberrations in certain neurotransmitters and neurotransmitter receptor functioning.

In 2009, Janssen et al. [14] published the first (quantitative) case-control association study in men with lifelong PE, defined in terms of an IELT of less than 1 min. Janssen et al. [14], investigated 89 men who actively soughted medical treatment for lifelong PE. In these men, the IELT was measured with a stopwatch. It was shown that the IELT duration in men with LPE is associated with 5-HTLPR polymorphism, indicating the presence of a disturbance of central serotonin neurotransmission, which is regulated by the activity of the 5-HT transporter. The study showed that the prevalence of LL, SL, and SS genotypes in LPE is comparable with the normal Dutch population. However, subjects with LL genotype (geometric mean IELT 13.2 s) ejaculated 100 % faster (p < 0.027) than men with SS genotype (geometric mean IELT 26 s) and SL genotype (geometric mean IELT 25.3 s) [14]. The strength of this study is that by using a stopwatch, accurate measurement of the IELT was performed which made it possible to find an association between the IELT and the investigated genotypes. However, a limitation of this case-control design is that by using this method one cannot investigate the influence of genetic polymorphism on the median IELT of about 6 min in the general male population. Interestingly, this finding is in line with pharmacological knowledge, indicating that a diminished serotonergic neurotransmission facilitates ejaculation.

From a statistical point of view it is just bad luck to have an IELT of less than 1 min, as this is just one end of the variability of the IELT in men in the general population. However, from a genetic point of view, there is now some preliminary evidence that the persistent short IELTs in men with lifelong PE may be due to genetic polymorphism of central serotonergic neurotransmission. And from a neurobiological point of view lifelong PE is possibly related to dysfunction of 5-HT_1A and 5-HT_2C receptors in brain areas that are specifically involved in ejaculatory functioning [10]. But what exactly is the problem in lifelong PE? Clearly, the neurophysiology of ejaculation itself is not disturbed in lifelong PE [15]. Rather, it is the timing of ejaculation that is persistently disturbed in men with lifelong PE [16]. And the timing of ejaculation is associated with a multitude of variables that have not yet been fully investigated. For example, how is timing related to the sensory information system of the peripheral and central nervous system? How is timing related to the motoric output system of both nervous systems? How is timing associated with genetic polymorphisms? The answers to these questions are essential for a deeper understanding of the pathophysiology of lifelong PE. New research into these questions is warranted. Sofar however, there are indications that the timing of ejaculation is related to the central nervous system.

Data derived from animal research suggest a major role of the central serotonergic system in modulating the spinal ejaculatory reflex [17]. This serotonergic modulation of ejaculation may result in a faster or more delayed ejaculation, whereas the ejaculation itself is probably not only under direct influence of the serotonergic system, but rather under the influence of other neurotransmitter systems in the spinal cord [16]. I would like to underline that this “modulation” is an important feature of the central serotonergic system that has hardly been discussed in the literature. However, it is pivotal for genetic research of PE and for a good understanding of the pathophysiology of lifelong PE. For example, it may be assumed that the modulation of ejaculation among men is variable; it can be strong, moderate, weak, or even absent. In the latter case, the serotonergic system in the brainstem is unable to modulate the ejaculation reflex in the lower spinal cord. In that case, a male is not able to or hardly able to change the duration of his ejaculation time; he has a rigid pattern of his ejaculation time without any variability. Even by using SSRIs, this person may still not be able to change the duration of his ejaculation time. Although never systematically investigated, it is clinically well known that a subgroup of men with lifelong PE do not respond with ejaculation delay to any SSRI treatment [16]. I therefore suggest that in these men, the serotonergic system is unable to modulate the ejaculation reflex [16]. The view that serotonin modulates ejaculation may have important implications for genetic and psychopharmacological research, because it may imply that in a certain cohort of men, an unknown number has no or hardly any ability to modulate ejaculation irrespective of the presence of functional serotonergic polymorphisms [16]. Consequently, irrespective of the presence of these polymorphisms, these men will not show any change in IELT duration when modulation of the IELT is not 100 % associated with such serotonergic polymorphisms.

Considered as a syndrome, i.e., as a cluster of symptoms, lifelong PE is characterized by the following symptoms [18]:

Based on clinical and epidemiological stopwatch data, Waldinger recently postulated the existence of two PE subtypes that had not been identified previously [19, 20]. Adding to lifelong and acquired PE, there are two other PE subtypes: (natural) variable PE and premature-like ejaculatory dysfunction or “Subjective PE”. The clinical symptomatology of the subtypes is different with regard to the duration of the IELT, the course of the IELT duration throughout life, the frequency of occurrence of short IELTs, and the cognitive experience of the IELT. Apart from the clinical symptomatology, the etiology and pathogenesis of the four subtypes is different [21]. Men with lifelong PE suffer from IELTs that are consistently less than 1 min since puberty or adolescence. Acquired PE may be caused by erectile dysfunction, thyroid disorders, acute inflammatory prostatitis or relationship problems [22–24]. In “Variable PE”, the IELT is only sometimes very short. In “Subjective PE” men have a normal or even long IELT duration, but still perceive themselves as having PE. It has been postulated that “Subjective PE” is strongly associated with psychological and cultural factors. Although there currently is no general consensus on the value of this new classification, Serefoglu et al. published two studies confirming the existence of the four PE subtypes in a Turkish population of men [25, 26].