While for impotence the list of etiological causes is large and growing, for PE the according list is still relatively short (Table 7.1), with the psychological causes being the most studied. Premature ejaculation has long been viewed exclusively as a psychological concern, although recent research also focuses on the organic underpinnings of the symptom [8].

Intrapsychic and relational derangement can be a risk factor for both LL- and A-PE, confirming that the two subsets of PE patients are not necessarily different in the pathophysiologic mechanisms. Hence, systematic use of psychopathological procedures is a determining aid in diagnosis of various PE subtypes [9].

Distortions of belief and false convictions about sexuality are established in childhood as a consequence of adverse influences on sexual behavior. Destructive attitudes are usually exerted by parents but also by other dominant persons within and outside the family [10]. This, in a Freudian perspective, may lead to sexual dysfunction such as PE.

Classic psychoanalytic theories identified a sadistic or narcissistic behavior in PE [11]. For other psychoanalysts, however, men who ejaculate prematurely are typically passive and masochistic in their marriage and obsessive–compulsive in character [12]. These theories were the basis of Helen S. Kaplan’s first idea, that PE is the result of an unconscious hatred of women [13, 14]. By ejaculating quickly, a man symbolically and physically “steals” the woman’s orgasm. However, the same researcher rejected her own theory when she found that men with PE do not have any particular neuroses or personality disorders [14].

Premature ejaculation has been considered frequent, if not normal, during early sexual experiences. To this concept, Masters and Johnson added other connected etiological causes: the risk of unwanted discovery (such as copulating in a car), experiences with prostitutes, and anxiety due to poor sexual education (e.g., absence of adequate knowledge of contraceptive methods) can worsen ejaculatory control, already physiologically poor at a young age [15].

Kaplan’s original etiologic explanation is also connected with the role of early experiences: the man with PE has not allowed himself to receive the sensory feedback of those sensations occurring immediately before orgasm which would enable him to bring his ejaculatory reflex under voluntary control [13]. She compares this etiologic mechanism to the control of enuresis obtained when a child recognizes the sensation of a full bladder. In the same way, lack of awareness of pre-ejaculatory sensations may lead to PE.

More recent findings correlate PE with psychological problems. Subject-reported personal distress most strongly indicated PE. Partner’s and personal distress better correlate with PE than IELT alone [16].

The role of anxiety (for sexual performance generally, but also for other, extrasexual reasons) has been frequently raised as a cause [17]. This is in keeping with Kaplan’s theory: anxiety may block pre-ejaculatory sensations. Premature ejaculation has been associated with a psychological state of mind measured by the hospital anxiety and depression scale (HADS) [18]. Furthermore, the role of anxiety has been seen as variable, interacting with the somatic vulnerability of the individual to determine orgasmic latency [19]. Finally, Corona et al. elegantly demonstrated high levels of free-floating anxiety in A-PE [20]. It should be noted, however, that anxiety may also be the effect rather than the cause of PE.

Social phobia can be a feature characterizing both LL-PE and A-PE. Premature ejaculation was the most common sexual dysfunction in male social phobic patients [21]. Moreover, PE was highly associated (p = 0.015) with social phobia, with an odds ratio of 2.55 [22].

Alexithymia is a deficit in identifying and communicating emotions that is presumed to play an important role in psychosomatic diseases. Alexithymic features, and in particular, an externally oriented cognitive style, can be seen as possible risk and/or maintenance factors for PE. Alexithymia could represent a variable to be assessed for an integrated diagnosis and treatment of PE [23].

In conclusion, the etiological approach of psychology to PE in general and to A-PE in particular should be re-thought. In fact, psychological involvement can be either a cause or may be caused by A-PE.

Although logical, the association between PE and hypersensitivity is still under debate. The sensitivity of the glans, the organ triggering ejaculatory reflex, undoubtedly has an important role in the ejaculatory mechanism, and possibly in some forms of PE. Penile sensation is unique when compared to other body regions [24]. The human glans penis is covered by stratified squamous epithelium and a dense layer of connective tissue, equivalent to the dermis of normal skin. The most numerous nerve terminals are free nerve endings (FNEs), which are present in almost every dermal papilla, as well as scattered throughout the deeper dermis. The FNEs are characterized by an incomplete Schwann cell investment and contain irregularly scattered neurofilaments and neurotubules, clusters of mitochondria, vesicles of variable size, and various inclusions. The unique corpuscular receptor of the glans penis consists of axon terminals that, at an ultrastructural level, resemble a tangled bunch of FNEs. Simple, Pacinian, and Ruffini corpuscles have been occasionally identified, predominantly in the corona glandis [25].

On this anatomical basis it has been shown that patients with PE, not necessarily with the acquired form, may have hypersensitivity and hyperexcitability of the glans penis, which may give rise to uncontrolled ejaculation and are believed to be organic implications for PE [26].

Evoked sacral potentials have in fact been used to study the bulbo-cavernous reflex in patients with PE [27]. In perineal and perianal measurements, the amplitudes of the evoked responses were much greater in these patients with respect to controls. This suggests a reflex hyperexcitability or an impaired “modulation” of the motor neurons of the pudendal nucleus in patients with PE. On the glans penis and penile shaft, the values in patients with PE have been found significantly less than those in normal potent men [28]. Furthermore, using somatosensory evoked potential, patients with PE showed a greater cortical representation of sensory stimuli from the genital areas than normoejaculators [29]. However, Rowland et al. found thresholds for premature ejaculators to be commensurate with controls, while men with erectile dysfunction or combined erectile dysfunction and PE showed significantly elevated thresholds [30]. Although patients with PE did not show penile hypersensitivity, there was a significant correlation in this group between ejaculation latency and threshold. Overall, these findings argue against a primary role for penile sensitivity in ejaculation latency, and suggest that other somatic factors or cognitive factors may play a more critical role in PE. Furthermore, faster conduction along the pudendal sensory pathway or a greater cortical representation of the sensory stimuli from the genital area or hyperexcitability of the BC reflex were not always confirmed in patients with PE [31]. This was further confirmed using a vibrometer with a precision and reproducibility higher than analog-type biothesiometers [32]. This suggests that the electrophysiological approach is probably not sufficient to clarify some causes of both LL- and A-PE. A more extensive investigation may give better results in this area [33].

Hormones play a central role in the machinery of emission–ejaculation [34]; this implies that pathological hormonal levels may directly or indirectly affect the ejaculatory control [35], as in the case of thyroid hormone, but may also be affected or simply modified by the condition of PE. This seems the case of testosterone and prolactin levels in A-PE.

The role of sex steroids Low serum testosterone levels have been inconsistently associated with PE [36, 37]. However, others have anecdotally suggested that hypogonadism can be considered a possible cause of delayed ejaculation (DE). Testosterone plays a crucial role in male sexual response, acting at both the central and peripheral levels, and is a clear determinant of motivation to seek sexual contact. Several studies in hypogonadal men have demonstrated that testosterone replacement has an unequivocal role in restoring sexual desire, spontaneous sexual thoughts and attraction to erotic stimuli. The testosterone dependency of type 5 phosphodiesterase (PDE5) expression and activity has also been demonstrated in other parts of the male genital tract (MGT) such as the vas deferens, a critical effector for semen emission and ejaculation [38]. Recent data suggest that testosterone plays a facilitatory role in the control of the ejaculatory reflex [39]. Different testosterone levels identify different subsets of ejaculatory disturbance. While a higher testosterone level characterizes PE, DE is associated with lower levels. Taken together, these data suggest a role for androgens in the mechanism of ejaculation [39].

Both central and peripheral mechanisms have been advocated to explain this association. The first explanation is psychoendocrinal. Testosterone level, in addition to its action on sexual response, profoundly influences male behavior. High testosterone levels in human adults are associated with leadership, toughness, personal power, and aggressive dominance [40]. Rowland considers DE to be essentially characterized by the uncoupling of a decreased subjective and a preserved genital reaction in sexual arousal [41]. It could thus be speculated that hypogonadism and related reduction in sexual confidence and aggressiveness could play a critical role in the control of ejaculation timing, reducing the internal cues for reaching orgasm and ejaculation.

The second hypothesis is neurological. Recent data from animal models seem to support the central action of testosterone in the control of the ejaculation reflex. Keleta et al. [42] demonstrated that long-term testosterone treatment in rats significantly decreased 5-HT in the brain. Another intriguing possibility involves the possible peripheral role of testosterone in regulating MGT motility. In rabbit hypogonadism, it was found that PDE5 is less expressed and biologically active in the vas deferens [43]. Testosterone administration completely reversed these alterations. Hence, it is possible that hypogonadism-associated DE is due to an increased inhibitory nitrergic tone on MGT smooth muscle cells. A “mechanical” action of testosterone in the ejaculation control can also be possible. A hypogonadism-induced reduction in semen volume may perturb the dynamics of the seminal bolus propulsion, possibly explaining ejaculation difficulties in some subjects. In fact, low testosterone directly reduces ejaculate volume, which may result in a lack of stimulation of accessory glands such as the prostate and seminal vesicles, which are well-known androgen targets. Finally, it cannot be excluded that the demonstrated testosterone differences are the consequence of sexual disturbances mirroring differences in sexual behavior, such as copulation frequency [44].

In conclusion, several possible mechanisms may connect androgen levels with the complex machinery of ejaculation. Clinical studies are currently in progress to further establish the role of testosterone in ejaculatory dysfunction.

The role of prolactin In a consecutive series of 2,531 patients interviewed using SIEDY structured interview (a 13-item tool for the assessment of erectle dysfunction-related morbidities) [45], and Middlesex Hospital Questionnaire [46], for the evaluation of psychological symptoms, low prolactin (PRL) levels are associated with PE and anxiety symptoms [47]. Low PRL seems an effect, rather than a cause of PE. In fact, many psychological disturbances (such as stress and frustration for chronic or acquired inability to enjoy sex) are able to provoke a neuroendocrine imbalance, such as that of the central serotoninergic system, mirrored by the relative hypoprolactinemia found in patients with PE.

The role of thyroid hormones The impact of thyroid hyper- and hypo-function in male sexual function has been studied only very recently. This is probably the consequence of: (i) the apparently low clinical significance given to male sexual symptoms in comparison with the systemic effects of thyroid hormone excess and defect; (ii) the paucity of clinical studies- as thyroid disease is less common in men; (iii) the embarrassment of patients and physicians when discussing sexual dysfunction in the “traditional” setting of the endocrine outpatient clinic [48]. However, a high prevalence of A-PE in hyperthyroid patients has been found, whereas in hypothyroid subjects the main sexual complaint was DE [20, 49]. Both ejaculatory dysfunctions reverted on achievement of euthyroidism in the absence of any other treatment for the sexual symptom. Interestingly, suppressed levels of TSH (as a marker of hyperthyroidism) have been demonstrated in A-PE [20] but, obviously, not in patients with LL-PE [50]. All these data suggest a direct involvement of thyroid hormones on the physiology of ejaculation.

As the relationship between thyroid hormones and ejaculatory mechanisms is currently unknown, three possible sites of action have been suggested: the sympathetic nervous system, the serotoninergic pathway, and the endocrine/paracrine system. Most manifestations of thyrotoxicosis and sympathetic nervous system activation overlap. This may suggest a similar action on ejaculation, a reflex largely dependent on sympathetic and parasympathetic tone. However, plasma catecholamines and their urinary metabolites are usually normal in hyperthyroidism [51]. On the other hand, some studies have found that thyroid hormones augment sensitivity to β-adrenergic agonists by increasing β-adrenoceptor density and G _s/G _i protein ratio through an over-activation of adenylate cyclase [52]. This leads to increased sympathetic activity with normal circulating catecholamine levels. In hyperthyroid patients, the increased adrenergic tone may trigger both PE and DE, either acting directly on smooth muscle contractility/relaxation or indirectly on anxiety and irritability. The opposite may occur in hypothyroid patients [53]. Considering the neuropsychological reactions to thyroid hormone excess (hyperkinesia, nervousness, anxiety, emotional lability), PE may be also a nonspecific disease-related complaint, disappearing when a euthyroid state is achieved. However, in light of the widespread distribution of thyroid hormone nuclear receptors within the brain, it can be hypothesized that iodothyronines specifically alter the central serotoninergic pathway [54], leading to diminished ejaculation control. In animals with experimentally induced hypothyroid states, increased serotonin turnover in the brainstem is consistently reported [55] and thyroid hormone replacement is associated with increased cortical serotonin concentrations and augmentation of serotonergic neurotransmission by desensitization of the serotonin inhibitory 5-HT_1A (auto-inhibition) [55]. Finally, DE is a common and therapeutically useful side effect of serotoninergic drugs, indicating that this pathway is fundamental for ejaculatory control.

Another way that thyroid hormones may affect the ejaculatory mechanism could be through estrogen metabolism. Hyperthyroidism increases levels of sex hormone binding globulin (SHBG), which binds androgens with higher affinity than estrogens, leading to a relative hyperestrinism. It has been demonstrated in hypogonadic rabbits that estrogens, but not androgens, fully restore oxytocin-induced epididymal contractility, up-regulating oxytocin receptor gene and protein expression, and that deprivation of endogenous estrogens induces oxytocin hyporesponsiveness [56, 57]. As oxytocin is closely involved in the ejaculatory mechanism [58], both centrally [59] and peripherally [60], this may account for the close correlation between hyperthyroidism and PE. As an ancillary possibility, thyroid hormone receptors have been described in the animal [61] and human testis [62], and may also be present in other male genital tract structures, triggering ejaculation. Finally, although excluded in the original report [49], some cases of PE in hyperthyroidism are comorbid with impotence, which may in turn exacerbate the loss of ejaculatory control [63].

Role of hormones in delayed ejaculation More insights on the role of hormones in the pathogenesis of A-PE can be obtained from experimental evidence produced on DE [64]. When comparing DE and PE, PRL as well as TSH levels progressively increased from patients with severe PE towards those with anejaculation. Conversely, the opposite was observed for testosterone levels. All of these associations were confirmed after adjustment for age. When these hormonal parameters are introduced in the same regression model, adjusting for age, general psychopathology and use of selective SSRIs, they are independently associated with ejaculatory problems [65]. This indicates endocrine system is involved in the control of ejaculatory function and that PRL, TSH (as a marker of thyroid activity), and testosterone play an independent role.

In conclusion, from a psychoneuroendocrine perspective, PE and DE can be considered two ends of a single continuum, spanning from severe PE to extreme DE (Fig. 7.1). In addition, although endocrine regulation of the ejaculatory reflex is still in its infancy, evidences so far produced indicates that it should grow rapidly to help in shedding light on often occurring but seldom-studied conditions like ejaculatory disturbances.

For unexplained reasons, the role of the largest gland involved in the mechanism of ejaculation has been ignored by the majority of urologists [66]. This is particularly surprising, since the main function of the prostate is to store and secrete the clear, slightly basic fluid that constitutes up to one-third of the volume of semen. The prostate also contains some smooth muscle that helps to expel its secretions during ejaculation.

The role of the prostate. The emission, the first phase of the ejaculatory process (see Chap. 3), is mediated by contractions of the smooth muscle in the capsules of the testes, seminal tract, and genital glands including the prostate [67]. It has been reported that electric waves discharged from the prostate at rest seem to produce prostatic contractions that appear to be responsible for increases in the prostatic urethral pressure [68]. Shafik [69] noted that, at ejaculation, the intermittent and significant increase in wave variables and urethral pressure coincided with the ejaculatory spurts and apparently denotes intermittent prostatic smooth muscle contractions. These prostatic contractions seem to squeeze the prostatic secretions into the prostatic urethra. However, some important experimental evidence are against the notion that the “distension” of the prostatic urethra by the entering semen is the probable trigger for the ejaculation reflex: (i) α-adrenergic blocking agents (phenoxybenazamine, phentolamine) prevent the discharge of semen into the urethra but they do not inhibit the initiation of ejaculation. This may occuralso in absence of fluid to ejaculate (dry orgasms) and without changes in the subjective experience of orgasm [70]. Moreover, healthy person could experience a dry emission/orgasm with a complete absence of secretions. (ii) it has been reported that a decrease in echogenicity of the prostatic urethra during the pre-ejaculatory phase signifies the secretion and movement of prostatic fluid to the prostatic urethra, which in turn leads to the inevitability of expulsion [71] and that prostatic urethra distendes 3–5 s before the start of seminal expulsion [72]; however, observing eight normal healthy volunteers, the expulsion of the contents of the seminal vesicles into the inframontanal urethra always occurs without prior ballooning of the prostatic urethra [73]. This may suggest that a “pressure chamber” does not appear to be formed before prostatic contractions take place. (iii) in copulating male rats, urethral stimulation by the ejaculate does not contribute to the activation of the striated muscle component of the ejaculation reflex [74], further suggesting that candidate sites for the ejaculation ‘‘trigger” could be present in the penile glans, spinal cord, and/or the brain.

Although the formation of the “pressure chamber” in the prostatic urethra is currently under debate, it is well know that the antegrade propulsion of seminal fluid into the distal urethra requires coordinated dynamic changes at the bladder neck, prostatic urethra, and external sphincter [75].

Effects of prostatic disorders on the ejaculatory process. Prostate inflammation/infections have been anecdotally correlated with PE in the past [76]. Jannini and coworkers firstly demonstrated, by the Meares and Stamey test [77], a relatively high prevalence of prostatic inflammations/infections in men with PE. Furthermore, it has been found that this sexual symptom is in turn common in subjects with prostatitis [78]. After this paper, the European Association of Urology (EAU) Guidelines on Ejaculatory Dysfunction recognized that “PE may be strictly organic (e.g. prostatitis-related)”, prescribing the rectal examination with evaluation of the prostate in patients with ejaculatory disturbances [79].

If a causal correlation exists, prostatic inflammation may alter sensations arising from the male genital tract, so that the male is unable to recognize the emission phase [80]. Prostatic inflammation/infections (variously demonstrated or simply admitted by patients in a population survey) has been found in a total of 3,115 patients with PE (variously defined) examined in several countries with a prevalence ranging from 15 to 64 % (Table 7.2).

Vice versa, PE has been found in 2,360 patients with prostatitis and/or lower urinary tract symptoms (LUTS) (Table 7.2). Note that LUTS have been also related with retarded/painful ejaculation [84, 85] (Table 7.3).

The possible relationship between prostatitis and PE is probably complex. Signs and symptoms of prostatitis have been found more common in patients with varicocele, who more often complain of PE [89]. On this basis, it has been suggested that PE should be considered a marker underlying organic diseases including varicocele. Chronic prostatitis could be the link between the two conditions.

One may argue that the correlation, if any, between prostatitis and PE can be mediated via the prostatitis-induced erectile dysfunction [90]. The physiological correlation between the machinery of erection and prostate is not fully understood. On the contrary, considering the physiological role of the prostate, the correlation between ejaculation and this gland is definitively robust. The possibility that the EP found in patients with prostatitis is due to erectile dysfunction cannot be ruled out, at least in patients with such a comorbidity (see later). However, several authors were able to cure PE just with a specific antibiotic treatment against the bacteria responsible of prostatitis [91–94].