Jason M. Scovell1 and Michael L. Eisenberg2
(1)
Center for Reproductive Medicine, Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
(2)
Department of Urology, Stanford University School of Medicine, Palo Alto, CA, USA
Michael L. Eisenberg
Email: eisenberg@stanford.edu
Keywords
Male sexual dysfunctionAnimal modelsNeuropeptidesMolecular imagingGenetic analysis
13.1 Prevalence of Male Sexual Dysfunction
Ejaculatory and orgasmic disorders are common in men. Data from the National Health and Social Life Survey collected in 1992 estimates that 13–17 % of men experience low libido, 7–9 % are unable to achieve orgasm, and 28–32 % experience premature ejaculation [1]. The lifetime prevalence of orgasmic disorder is much greater in HIV-positive homosexual men (20–38 %) when compared to their heterosexual counterparts (0–9 %), highlighting the psychological contributions to sexual dysfunction [2, 3]. Ejaculation and orgasm are complex processes that integrate numerous neural, psychological, and physiological processes and are challenging to study. In this chapter, we discuss the current understanding of these processes and the use of state-of-the-art approaches, including animal models, neuroimaging, and genomic analysis, to better define the mechanisms of human ejaculation and orgasm.
13.2 Animal Models
Studying sexual function can pose many challenges, as sexual activity is often private and may involve multiple individuals. Animal models provide an avenue to study some of the underlying mechanisms of sexual function and dysfunction without the potential taboo of using human subjects. However, it is important to understand that findings from animal models may not always translate to the complex physiological and psychological aspects of human sexual behavior. Much of our understanding of the neurobiology of sexual behavior and function has been derived from rat models [4]. Because rats can achieve up to five ejaculations in a 30-min period, they have been proven as an effective model to test various pharmacological treatments for ejaculatory and erectile disorders. These studies have also contributed to our understanding of the neuroanatomical and neurochemical pathways important for ejaculatory response [5–8]. Our understanding of the roles of neurotransmitters and neuropeptides , including serotonin, dopamine, oxytocin, and prolactin, has largely arisen from studies in rat models [5, 6, 8, 9].
13.3 Neuroanatomical Modeling
Studying the neuroanatomical pathways involved in human sexual function has been limited by available techniques. Approaches have included the use of animal models [10], patients with epileptic seizures with sexual features, and the study of patients with localized brain lesions resulting in sexual symptoms [11]. Another approach has been to evaluate the effects of neurological surgery on various functional regions of the brain [12–15]. The advent of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has played an integral role in our understanding of the neurological pathways involved in sexual arousal and orgasm. These techniques have enabled the noninvasive study of normal, healthy individuals as well as patients with sexual dysfunction. fMRI and PET imaging permit site-specific and whole-brain investigation of both the neuroanatomical pathways and the cognitive aspects of sexual function via evaluation of brain regions with increased blood flow or metabolic activity, measured as regional cerebral blood flow (rCBF) [16]. Furthermore, both approaches have a spatial resolution down to ~1–3 mm, and both provide almost real-time temporal feedback (fMRI, 2–3 s; PET, 1 min). These studies have permitted the identification of the association between male ejaculation and orgasm and brain structures including the prefrontal cortex, the ventral tegmental area, and the cerebellum [17, 18]. A deeper understanding of the neuroanatomical pathways and their response to various stimuli will be useful in identifying the underlying pathophysiology of various sexual disorders and may provide a more targeted approach for either pharmacological or psychological therapy.
13.4 Genomic Techniques
As technologies to investigate genetic variation become increasingly cost- and time effective, these techniques can provide insights into the pathways important in ejaculation and orgasm. Over the past decade, these high-throughput technologies have been instrumental in identifying single nucleotide polymorphisms (SNPs) and gene copy number variations (CNVs), permitting ever more rapid and accurate investigation into the genetic changes that underlie numerous conditions, particularly when applied using next-generation sequencing techniques that permit evaluation on a genome-wide level. SNP analysis allows for rapid and affordable screening of many patients for known nucleotide polymorphisms and can identify genetic alterations that may lead to changes in protein concentration or function, facilitating the association of these small genetic alterations with various clinical phenotypes. These approaches can be used to identify novel pathways and to add to our understanding of already described processes. Several studies have utilized SNP arrays in various populations to identify candidate genes important for sexual function, including the serotonin and dopamine receptors, as well as genes in the glutamatergic pathway [19–21]. These are discussed in more detail below.
13.5 Pathways in Ejaculation and Orgasm
Ejaculation is classically divided into three phases: emission, ejection (expulsion), and orgasm. The ejaculatory reflex occurs via communication between sensory receptors, cerebral sensory areas, spinal motor pathways, and efferent neural pathways. Proper function requires a complex interplay between many different types of neurotransmitters including serotonin, dopamine, acetylcholine, oxytocin, nitric oxide (NO), norepinephrine, and gamma-aminobutyric acid (GABA) [22]. Seminal emission is mediated via sympathetic nerves originating from T10 to L2. Coordinated contractions of the seminal vesicles and the prostate gland transfer sperm and seminal fluid into the posterior urethra. Ejection is then stimulated via somatic nerves originating from S2 to S4 and occurs through coordinated contractions of the bulbocavernosus and pelvic floor muscles, together with relaxation of the external urinary sphincter (Fig. 13.1). Simultaneously, intermittent contraction of the urethral sphincter prevents retrograde flow into the bladder [22, 25, 26].
Fig. 13.1
Neural signal integration in the control of ejaculation in rats. Parasympathetic fibers project from the spinal ejaculation generator (LSt) to the sacral parasympathetic nucleus (SPN). Sympathetic fibers are projecting from the LSt to the dorsal gray commissure (DGC) and the intermediolateral cell column (IML). Sympathetics travel to the seminal tract by projections through the lumbar sympathetic chain (LSC) to the superior hypogastric plexus (SH) and then onto MPG. The bulbospongiosus (BS) motor neurons responsible for expulsion will travel to the BS muscle through the motor branch of the pudendal nerve (PudN). HN, hypogastric nerve [23]. With permission from Giuliano F, Clement P. Serotonin and premature ejaculation: from physiology to patient management. Eur Urol. 2006; 50:454–466 [24]
Control centers in the central nervous system (CNS) serve to regulate ejaculation. Structures including the posteromedial bed nucleus of the stria terminalis, the posterodorsal medial amygdaloid nucleus, the posterodorsal preoptic nucleus, and the parvicellular portion of the subparafascicular thalamus serve to inhibit ejaculation (Fig. 13.2) [27]. Molecular imaging techniques have been used to evaluate the brain for regions involved in ejaculation. One study recorded rCBF during ejaculation aided by the participant’s female partner so as to minimize background noise that would have otherwise been generated by manual stimulation [18]. The authors utilized PET with a scanning interval of ~10 min, and participants performed various tasks including rest, erection, sexual stimulation, and ejaculation while their head was restrained using an adhesive band. During ejaculation, the scanning interval was shortened to 10 s. During ejaculation, the primary activation was found to be in the mesodiencephalic transition zone that includes the ventral tegmental area, which is involved in the reward pathway. A variety of other mesodiencephalic structures were also found to be activated. Interestingly, neocortical activity was increased exclusively on the right side during ejaculation. In this study, the cerebellum, involved in emotional processing, demonstrated high levels of activation [17]. However, subsequent studies have suggested that the most important events involve deactivation throughout the entire prefrontal cortex, a region critical for higher-order functions that include, but are not limited to, both self-control and working memory [17]. This finding is supported by reports documenting disinhibition and hypersexuality in individuals with damage to the prefrontal cortex [28, 29], as well as other studies demonstrating that reduced cortical activity in the prefrontal cortex associates with male sexual arousal [30]. Studies using PET imaging are limited by their suboptimal temporal resolution (~1 min) given the short duration of ejaculation, and fMRI data to assess male orgasm and ejaculation remain limited. One study utilizing fMRI to study ejaculatory function primarily focused on sexual satiety and suggested that the refractory period following ejaculation may be due in part to neuronal activation of the temporal lobes, septal areas, and amygdalae [31].
Fig. 13.2
Locations and pathways of the inhibitory central pathways of ejaculation. Gray structures are mediated by serotonin auto-/heteroreceptors. SPFp, parvicellular part of the subparafascicular thalamus; MeAPD, posterodorsal medial amygdala [23]. With permission from Giuliano F, Clement P. Serotonin and premature ejaculation: from physiology to patient management. Eur Urol. 2006; 50:454–466 [24]
Orgasm is the result of CNS processing of pudendal nerve sensory signals. Stimuli for orgasm include increased pressure in the posterior urethra, signals originating at the verumontanum, and contractions of the urethral bulb and accessory sexual organs [25]. Molecular imaging has been used to study the male orgasm and has found increased rCBF only in the right prefrontal cortex with global decreases in all other cortical regions [32]. Although current data support the roles of different neuronal regions in orgasm, there remains a need for a more complete understanding of the neuroanatomical pathways involved in the process before a cohesive understanding is reached.
Several studies have applied genomic techniques to identify candidate genes involved in male sexual dysfunction. In a small study, men with a history of depression being treated with selective serotonin reuptake inhibitors (SSRIs) were evaluated using SNP analysis to identify potential genetic risk factors for SSRI-induced sexual dysfunction [33]. Men between the ages of 18 and 40 without sexual dysfunction prior to initiation of therapy were included in the study cohort. Sexual dysfunction was evaluated using the validated self-administered Changes in Sexual Functioning Questionnaire (CSFQ) which measures changes in sexual functioning or desire [34]. The authors investigated the pharmacogenetic candidate 5-HT2A–1438G/A and a polymorphism in the gene encoding the beta subunit of its G-protein second messenger GNB3 C825T using polymerase chain reaction (PCR) amplification and subsequent pyrosequencing [35]. Bishop and colleagues found that a SNP in the gene coding for 5-HT2A was associated with decreased desire/frequency and arousal in females, although this did not reach statistical significance in the male cohort. Despite the limitations of this study, including its retrospective nature, use of a self-administered questionnaire to assess changes in sexual function, and small sample of males included in the study, this work demonstrates the utility of identifying genetic risk factors and their potential impact on various aspects of sexual dysfunction.
A relationship between a SNP in the gene encoding the dopamine D2 receptor and sexual dysfunction in the male schizophrenic population on antipsychotic monotherapy (clozapine, risperidone, chlorpromazine, haloperidol, olanzapine) has also been observed [20]. Zhang and colleagues analyzed four candidate polymorphisms in two genes coding for the dopamine D2 receptor and endothelial nitric oxide synthase (DRD2, eNOS). Sexual symptoms were evaluated using the Arizona Sexual Experience Scale (ASEX) [36] and the five-item version of the International Index of Erectile Function (IIEF-5) [37]. Only the polymorphism DRD2–141C Ins/Del was associated with a lower overall ASEX score as well as lower scores in the arousal, penile erection, and orgasm (ability) questions. There was also an association between this polymorphism and a man’s ability to obtain and maintain an erection.
Genes involved in the glutamatergic pathway (GRIA3, GRIK2, GRIA1, GRIN3A) have also been associated with sexual dysfunction using SNP analysis in patients with major depressive disorder (MDD) treated with citalopram [21]. These data come from a subset analysis of the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was a large multicenter prospective trial including 4041 outpatients aged 18–75 at 41 clinical sites throughout the United States being treated for MDD. The primary goal of this study was to identify the effectiveness of various MDD treatment modalities [38]. The analysis performed by Perlis and colleagues focused on 68 genes chosen by expert consensus in several known pathways (serotonergic, glutamatergic, dopaminergic, adrenergic, neurotrophic, and others). The authors evaluated mutations in the entire gene as opposed to individual SNPs so as to account for linkage disequilibrium and to identify genes that may be altered by SNPs. GRIN3A, a gene encoding for a glutamate receptor, had the strongest association with difficulty in achieving erection. Similar to the previous study by Bishop and colleagues, mutations in the serotonergic receptor 5-HT2A were also associated with erectile dysfunction. Mutations in two other genes encoding receptors in the glutamatergic pathway (GRIA3 and GRIK2) carried an increased risk of 20–30 % and 30–40 % for decreased libido. An association with orgasmic difficulty was also found with GRIA1, another glutamate receptor. This study highlights the potential importance of the glutamatergic pathway on antidepressant-associated sexual dysfunction, which has not been studied in humans.
Kurose and colleagues performed a prospective genome-wide association study (GWAS) to evaluate the relationship between various SNPs and SSRI-induced sexual dysfunction [39]. Patients with MDD who were naïve to SSRI therapy or patients on SSRI therapy who underwent a 10-day washout period were included in the study and given paroxetine, fluvoxamine, or milnacipran. Sexual dysfunction was defined as decreased libido, delayed ejaculation, delayed orgasm, or erectile dysfunction. Genomic analysis was performed using a SNP array that identified 262,264 known SNPs, and 201 unrelated patients (106 male) were included for analysis. The authors identified 16 SNPs associated with sexual dysfunction, and of these 11 (69 %) were located in the gene encoding for the MAM domain-containing glycosylphosphatidylinositol anchor 2 (MDGA2) protein. This gene and its product are not well described, but this study shows the potential value of identifying novel pathways involved in sexual dysfunction. Other studies have been less successful in linking SNPs to various sexual dysfunctions [40, 41].
13.6 Diminished Ejaculation Disorders
Diminished ejaculation disorders are a subset of male orgasmic disorders encompassing altered ejaculation and/or orgasm and include reduced semen volume, retrograde ejaculation, decreased force and sensation of ejaculation, and altered ejaculatory latency [42]. Ejaculatory latency is defined as the time it takes for a man to achieve ejaculation. For research purposes, this is often defined as the intravaginal ejaculation latency time (IELT) , which utilizes vaginal penetration as the starting point from which latency time is measured. Some men struggle with the duration of their ejaculatory latency time which spans from premature to delayed to anejaculation. According to the Waldinger neurobiological hypothesis of ejaculatory control, these disorders are at the extremes of the same continuum [43]. The causes of ejaculatory latency dysfunction are numerous and include iatrogenic, psychological, and genetic. While the iatrogenic causes of ejaculatory latency dysfunction are well described, by definition, the idiopathic causes are often not well understood.
A panel of experts convened by the International Society for Sexual Medicine (ISSM) defines premature ejaculation (PE) as “…ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration, the inability to delay ejaculation on all or nearly all vaginal penetrations, and the presence of negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy [44].” Evidence from several trials suggests that >80 % of men with lifelong PE have intravaginal ejaculatory latency times under 1 min, with the balance ejaculating in under 2 min. It is important to note that most studies are limited to heterosexual men engaging in vaginal intercourse [44]. In general, PE can be classified into two main forms: (1) lifelong (primary) and (2) acquired (secondary). The latter occurs later in life and may accompany erectile dysfunction (ED), and data suggest that up to half of men with ED also have PE [45–47].
The prevalence of PE can vary based on cultural norms and practice as well as whether or not the data come from subject self-report versus clinician diagnosis. Two commonly quoted sexual surveys estimate the prevalence of PE between 20 and 30 %. The international Global Study of Sexual Attitudes and Behaviors (GSSAB) reported a prevalence of 30 % across all age strata [45, 48], and the Premature Ejaculation Prevalence and Attitude Survey identified a rate of 23 % among men 18–70 years old [47].
Delayed ejaculation and anejaculation is poorly understood, with few studies focused on these disorders [49]. Unlike PE, delayed ejaculation is relatively rare with a prevalence of ≤3 % [42]. The etiology of delayed ejaculation is often idiopathic, although various iatrogenic causes including nervous system disorders (i.e., multiple sclerosis, diabetes mellitus, spinal cord injury) as well as drugs that affect the α-adrenergic pathway may result in delayed ejaculation [50–52]. The causes of delayed ejaculation can sometimes be identified as pathological as opposed to pathophysiological, suggesting a known etiology and a potentially treatable disease [53]. Unfortunately, the majority of cases are idiopathic, and discerning whether or not the cause is due to genetic and developmental factors as opposed to pathological disease processes is not possible. Although many hypothesize that genetics may play a role in determining a man’s ejaculatory latency, a Finnish twin study suggests otherwise, finding only an influence of genetics on premature ejaculation and no genetic influence on delayed ejaculation [54].
Many of the known physiological factors influencing ejaculatory latency involve age-related changes. A decrease in penile sensitivity that develops during the male aging process is a likely contributor to delayed ejaculatory latency [55, 56]. Similarly, changes in the sensitivity of the ejaculatory reflex pathway may increase the time it takes for a man to achieve ejaculation. As discussed above, the interplay between the physical response pathways and the psychological control processes driving orgasmic and ejaculatory function is complex, and impairment of the central cognitive arousal pathway is another likely driving factor in increased ejaculatory latency [57].
Reduction or absence of ejaculate volume is another component of ejaculatory dysfunction. The majority of decreased or absent semen volume with ejaculation is due to anatomical defects, which include both congenital and acquired conditions. The most common etiology for low semen volume is retrograde ejaculation secondary to a transurethral resection of the prostate for benign prostatic hyperplasia. Other anatomical causes of decreased semen volume include defects of the nervous system, obstruction, and hypogonadism [58]. Very few studies exploring the relationship between genetics and semen volume are available. The positive relationship between GGN repeats in the androgen receptor gene and semen volume was demonstrated in a study from Sweden evaluating 220 adolescent Swedish men. Men with <23 GGN repeats had a decreased semen volume when compared to men with 23 GGN repeats (−0.6 ml, p = 0.02) and when compared to men with >23 GGN repeats (−0.9 ml, p = 0.002) [59]. This finding was replicated in the Latvian population with similar results. An effect of paternal origin (Latvian versus non-Latvian) on semen parameters was also shown to exist. Men with Latvian fathers had a greater sperm concentration and total sperm counts when compared to men born to non-Latvian father [60]. These data suggest a role of genetic variation in the androgen receptor gene on semen volume. Variation in other genes important in seminal fluid production has yet to be investigated, but it is tempting to speculate that semen production and volume are a function of numerous genetic variations present throughout the population.
The precise etiology of ejaculatory latency dysfunction is uncertain but likely involves the complex interplay between neurochemical, anatomic, psychological, and environmental factors. One proposed mechanism states that abnormal serotonin neurotransmitter signaling underlies altered ejaculatory latency. This hypothesis is based on the observation that stimulation of 5-HT1A receptors results in shortened ejaculatory latency in rats [61]. These findings are supported by the fact that treatment with SSRIs can result in a delayed ejaculatory response in humans, suggesting that serotonin is an important factor in the male ejaculatory response [62].
Animal models have allowed researchers to study the complex role of serotonin in sexual behavior. Through a combination of SSRIs , 5-HT receptor agonists and antagonists, receptor subtypes 5-HT1Aand 5-HT1B, have been identified as critical in ejaculatory function. Differential action at these receptors modulates ejaculation in opposing directions [63–66]. Antagonism at the 5-HT1A receptor delays ejaculation, whereas agonism at the 5-HT1Breceptor increases ejaculatory latency. However, our understanding of the role of serotonin on ejaculatory function remains limited. One hypothesis is that some SSRIs delay the ejaculatory response through activation of serotonergic receptors in specific brain or spinal cord regions, while those SSRIs that do not seem to affect time to ejaculation (i.e., citalopram, fluvoxamine) may not act on these receptors [4].
Alternatively, cellular and neuroendocrine pathway alterations may drive the delayed ejaculatory response seen in chronic SSRI administration. In rats, a time-dependent administration of fluoxetine and paroxetine reduces oxytocin, adrenocorticotropic hormone (ACTH), and corticosterone levels in response to a 5-HT1A agonist. In these studies, there was no change in 5-HT1A receptor density in any region of the brain. However, levels of the Gi1and Gi3 proteins, G-protein subunits important in stimulating downstream signaling pathway inhibition and activation, in the hypothalamus were reduced. Thus, it appears that 5-HT1A receptors are desensitized by some SSRIs, and this desensitization may be through decreased levels of hypothalamic G-proteins [67, 68]. More specific targeting and modulation of 5-HT receptor subtypes will improve the ability to identify therapeutic targets for premature ejaculation and to avoid the potential unwanted side effect of delayed ejaculation in men with depression and normal ejaculatory latency.
SNP analysis has linked polymorphisms in the 5-HT2C receptor that have been linked to men with lifelong premature ejaculation [19]. This technique has also identified an association between premature ejaculation and a mutation in the oxytocin receptor (OXTR), supporting the role of oxytocin in ejaculatory latency [69]. In this study Jern and colleagues studied 1517 male twin and non-twin brothers between the ages of 18 and 45 years old as a subset analysis of a larger study entitled the Genetics of Sex and Aggression, a population-based study of Finnish twins and their siblings [54]. This study looked at SNPs in the oxytocin and arginine vasopressin 1A and 1B receptor genes and their association with PE. Premature ejaculation was quantified using four questions asking about ejaculatory latency time, number of thrusts before ejaculation, frequency of anteportal ejaculation, and ejaculatory control. One SNP in OXTR (rs75775) was associated with differences in self-reported ejaculatory latency and perceived ejaculatory control. These findings strengthen our understanding of the role of hormonal signaling in PE.
13.7 Summary
The mechanisms underlying male ejaculatory and orgasmic disorders are not well characterized, but appear to be undergoing a renaissance due to the use of novel, contemporary techniques in their study. Animal models and patients with localized brain lesions have provided much of our understanding about the neuroanatomical and biochemical pathways important for ejaculation and orgasm. With the emergence of noninvasive techniques including molecular-level brain imaging and genetic analysis, there are opportunities to strengthen our current understanding and identify novel pathways that can lead to improved therapies. There is ample opportunity and significant need for these studies to better characterize the anatomical and physiological components required for normal ejaculatory and orgasmic function.
Commentary: Underlying Principles in Ejaculatory and Orgasmic Function and Dysfunction in the Male
Marcel Waldinger3, 4
(3)
Division Pharmacology, Department of Pharmaceutical Sciences, Faculty of BetaSciences, Utrecht University, Utrecht, The Netherlands
(4)
Practice for Psychiatry and Neurosexology, Amstelveen, The Netherlands
Human ejaculatory and orgasmic control pathways are complex and our understanding of these mechanisms is still in its nascency—this is made clear in the preceding chapter by Scovell and Eisenberg. However, the growing use of sophisticated technologies to map brain regions involved in conscious and subconscious processes, including ejaculation and orgasm, and the application of cutting-edge genomic technologies to better understand how our genetic milieu regulates how we respond to sexual stimuli, are improving our grasp of these conditions faster than ever before. Nevertheless, as Waldinger astutely highlights in the following commentary, detailed observation of men with ejaculatory problems can identify details that can lead to novel classifications of these disorders. It is this intersection between sophisticated technologies that can identify molecular factors that affect ejaculation and orgasm, combined with the human touch and close observation that can parse the vagaries of these conditions that will truly permit us to understand ejaculatory and orgasmic dysfunction. With this detailed understanding will then come the ability to effectively intervene, whether it’s using pharmacotherapy, surgery, or other therapies in the quiver of the mental health specialist.
The Editors
Commentary
In the last two decades, substantial progress has been made in understanding ejaculatory and orgasmic disorders. In vivo animal research, human clinical research, and brain imaging studies have contributed to a better neurobiological understanding of particularly premature ejaculation (PE) [1–4]. Despite this progress, for many sexologists, research and treatment of PE seem to have started (and ended) in the 1960s with Masters and Johnson, who advocated behavioral therapy in the form of the squeeze technique to the penis applied by the female partner [5]. It is still generally believed that oral drug treatment is a relatively new concept in the treatment of PE, starting with the introduction of monoamine oxidase inhibitors (MAOIs), mellaril, and clomipramine during the 1970s and becoming particularly popular since the introduction of SSRIs and dapoxetine during the 1990s [6].
In this commentary, two new concepts in the understanding of PE, particularly lifelong PE, will be reported and explained. Intriguingly, the roots of one of these concepts were partly formulated in the 1940s, but subsequently largely ignored and forgotten.
The First PE Research and the First Oral Drug for PE
Research exploring PE started long before Masters and Johnson suggested that PE was the result of self-learned behavior [7]. In 1917, the well-known psychoanalyst Karl Abraham called it “ejaculatio praecox” and postulated that it was the manifestation of unresolved unconscious conflicts [8]. However, he never systematically investigated this hypothesis. It was Bernhard Schapiro who investigated a very large number of men with complaints of PE in the 1920s and 1930s at the Institut fur Sexualwissenschaft in Berlin [9]. In the 1920s, he developed Präjaculin, which was the first oral drug for the treatment of lifelong PE [10]. Präjaculin was produced by the German company Promonta in Hamburg from 1932 until the mid-1960s [10]. In other words, oral drug treatment for PE was available more than a decade before even the first review article on PE was published by Schapiro and more than 40 years before Masters and Johnson published their squeeze technique. Bernhard Schapiro is not only the true pioneer in the research of PE; his findings, as published in 1943, are still valid today and have, 70 years after publication, also become the basis for a new concept in the understanding of PE.
Erectio Praecox
Essential to the ideas of Schapiro on PE is that he listened very carefully to the details his patients reported on PE. In this way, he was able to distinguish two PE subtypes: lifelong and acquired. At the time he called them the hypertonic (lifelong PE) and hypotonic (acquired PE) types [9]. Schapiro also noticed that, in contrast to men with acquired PE, men with lifelong PE reported little difficulty in obtaining erections [9]. He called this “erectio praecox” [9]. Notably, after his 1943 publication, the term “erectio praecox” was never quoted in the sexological literature until 2002, when Waldinger reintroduced the term, highlighting that many men with lifelong PE report this phenomenon and that it may be related to central oxytocin release [11]. However, the primary complaint of men with lifelong PE is the persistent early ejaculations. Often, these men are not even aware of how easily they achieve erections, and this is reported to the physician by their female partners.
Detumescentia Praecox
Waldinger recently reported that men with lifelong PE often have an acute and complete penile detumescence after ejaculation [12]. He called this phenomenon “detumescentia praecox” [12]. Similar to erectio praecox, this rapid penile detumescence is hardly expressed as a complaint, as men with lifelong PE are accustomed to it. Still, both phenomena should be regarded as subtle rather ego-syntonic manifestations of lifelong PE.
Hypertonic State
The presence of rapid erection and/or penile detumescence shows that lifelong PE is not only a matter of persistent early ejaculations, as believed for so many decades. As soon as these men become involved in an erotic or sexual situation, they become unwantedly overwhelmed by a “hypertonic state,” an acute physical/genital state of sexual/genital hyperarousability with premature ejaculation and/or facilitated erection and/or facilitated penile detumescence [12]. This new concept, as recently formulated by Waldinger, has important consequences for the approach and treatment of men with lifelong PE.
Classification of Four PE Subtypes
Based on stopwatch measurements of the intravaginal ejaculation latency time (IELT), stopwatch-mediated epidemiological studies of the IELT, and the occurrence of PE throughout life and the frequency of complaints, Waldinger and Schweitzer proposed a new classification of four PE subtypes: lifelong PE, acquired PE, subjective PE, and variable PE [13–15]. In contrast to the very short IELTs of lifelong and acquired PE, men with subjective PE have normal or even long IELTs [16]. In variable PE, the complaints of PE occur only sometimes [16]. The hypertonic state is characteristic for lifelong PE, whereas a hypotonic state characterizes acquired PE. Subjective PE and variable PE are characterized by a normotonic state [16]. Erectio praecox and detumescentia praecox only occur in lifelong PE [12, 17].
Advantages of the New PE Classification
A major advantage of the new classification system is that males with all IELT values can be classified into one of the four PE subtypes. Yet, the new classification system also demands the existence of factors other than the IELT. By using this system, classification no longer depends on the (subjective) mental/emotional state of a man complaining of PE, but on concrete physical symptoms.
Treatment Differences Among the Four PE Subtypes
The different clinical symptoms and genital/physical tonus of the four PE subtypes obviously affect the emotions and mental coping mechanisms of these men. However, the emotional and psychological burdens in these men also depend on factors unrelated to the specific PE subtype. In other words, psychological and emotional factors are inadequate to identify and group males into the four subtypes, as affected men may suffer to the same emotional extent. Indeed, the duration of the IELT, the course in life, the frequency of occurrence, and the presence of erectio praecox and detumescentia praecox are the most important factors allowing distinction between the four PE subtypes. This is clinically relevant, as the current ISSM [18] and DSM-5 definitions [19] of PE in terms of (1) IELT duration, (2) extent of ejaculatory control, and (3) negative personal consequences appear to be inadequate to encapsulate all four PE subtypes.
Counseling and Psychoeducation
The ability to distinguish the four PE subtypes is relevant for both treatment and research. Drug therapy is frequently essential for lifelong PE and acquired PE. Preferably, this drug treatment by daily or on-demand use of oral drugs is accompanied by psychoeducation on PE and the positive and adverse effects of the drugs. Treatment of “subjective PE” should consist of counseling and psychoeducation with specific attention toward psychological and cultural factors that contribute to the conviction of a man with a normal/long IELT duration that he suffers from PE. Counseling and psychoeducation are also important for “variable PE,” which is a normal variant of human ejaculatory performance. Notably, local anesthetic creams or sprays may also be indicated for men with both subjective and variable PE. It might well be that behavioral treatment in the form of the stop/start or squeeze technique will have better outcomes in subjective PE than so far has been found in lifelong or acquired PE. Future research is therefore warranted.
Psychoanalytic Research
Another issue of PE that has been often overlooked in our times is the psychodynamic consequences of PE. The new classification may constitute a solid basis for renewed psychodynamic research. The fact that lifelong PE is currently thought to be substantially influenced by neurobiological and genetic factors should not be an impairment for psychoanalytic research of these men. Psychoanalytic treatment in brain-damaged patients is one of the core elements of neuropsychoanalysis [20–22]. In this respect, (neuro)psychoanalytic analysis of men with PE, particularly those with lifelong PE, would be extremely interesting and even more so when compared with work evaluating men with subjective PE. In addition, other psychological schools of thought would each shed an improved understanding of psychosocial-behavioral and cultural components of PE etiology and impact on both men and their partner. In particular for this author, the need for additional psychoanalytic evaluation of PE is clear, not only to better understand men for in whom PE has become part of a neurotic behavioral pattern but also to elucidate epigenetic and genetic factors that contribute to the expression or maintenance of PE.
13.1 Genetic Research of the IELT
In the last decade, genetic research examining IELT in men with lifelong PE, combined with stopwatch measurements of their IELTs, has shown that persistent short IELTs are associated with at least three genetic polymorphisms of the 5-HTT gene, the 5-HT1A receptor gene, and the 5-HT2C receptor gene [23–27]. This genetic research focused on the central serotonergic system that mediates ejaculation in both male rats and humans [28]. However, the new concept of the hypertonic state in lifelong PE implies that lifelong PE is not just associated with the central serotonin system [12]. Accepting erectio praecox and detumescentia praecox as part of the phenomenology of lifelong PE implicates that other neurotransmitter systems (e.g., dopamine, oxytocin) and hormonal factors (e.g., testosterone, prolactin) also play an important role in lifelong PE [12].
Conclusion
In conclusion, according to a newly formulated concept, lifelong PE is no longer solely characterized by persistent, very short IELTs, but also by rapid erections, rapid penile detumescence, and an acute hypertonic state. Another new concept is the identification and classification of four PE subtypes. This classification system is organized such that men with all IELT values and also complaints of PE can be described. Most essential for new theoretical discoveries on PE remains the listening ear of the clinician who preferably must also have a critical mind and the gift to note subtle symptoms as very relevant for diagnosis, treatment, and research.
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