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Etiology of Ejaculation and Pathophysiology of Premature Ejaculation
Blackwell Publishing IncMalden, USAJSMJournal of Sexual Medicine1743-6095© 2006 International Society for Sexual Medicine20063S4303308Original ArticleEtiology of Ejaculation and Pathophysiology of PEDonatucci
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Etiology of Ejaculation and Pathophysiology of Premature Ejaculation Craig F. Donatucci, MD Division of Urology, Duke University Medical Center, Durham, NC, USA DOI: 10.1111/j.1743-6109.2006.00305.x
ABSTRACT
Introduction. Ejaculation is comprised of three stages of the male sexual response cycle, namely emission, ejection, and orgasm; however, in comparison with erection, which is a well-understood component of male sexual response, the pathophysiology of ejaculation has yet to be fully delineated. Premature ejaculation (PE), the most common sexual disorder in men, while believed to have a multifactorial etiology, is even less well understood. Aim. This article reviews the physiology of ejaculation, and the multifactorial pathophysiology of PE. Methods. The Sexual Medicine Society of North America hosted a State of the Art Conference on Premature Ejaculation on June 24–26, 2005 in collaboration with the University of South Florida. The purpose was to have an open exchange of contemporary research and clinical information on PE. There were 16 invited presenters and discussants; the group focused on several educational objectives. Main Outcome Measure. Data were obtained by extensive examination of published peer-reviewed literature. Results. Evidence supports that biologic mechanisms associated with neurotransmitters such as norepinephrine, serotonin, oxytocin, Gamma-amino-butyric acid, and nitric oxide (NO) as well as the hormone estrogen play central roles in ejaculation, and subsequently may mediate PE. There is also emerging evidence to show that hyperthyroidism may be a causal factor in PE. Recent data also suggest that psychogenic factors include high level of any experience by some men with PE. Conclusions. The pathophysiology of both lifelong and acquired PE appears to be both neurobiogenic and psychogenic. While psychogenic factors appear to be contributory to PE, pharmacologic intervention of PE can modify intravaginal ejaculatory latency time (IELT), which suggests that IELT is a biological variable, and is likely biologically dependent upon neurotransmitters and hormones. Donatucci CF. Etiology of ejaculation and pathophysiology of premature ejaculation. J Sex Med 2006;3(suppl 4):303–308. Key Words. History of Sexual Dysfunction; Premature Ejaculation; Epidemiology
The Physiology of Ejaculation
A
lthough ejaculation has traditionally been thought of as a single event, in fact, it comprises three separate and distinct components: emission, ejection, and orgasm. Further, they involve separate neural pathways [1] (Figure 1). Antegrade ejaculation begins with emission, which is a sympathetically mediated (thoracic 10 to lumbar 2) neural function that acts through alpha-adrenergic receptors [2,3]. Emission leads to the contraction of seminal vesicles and the prostate with expulsion of sperm and seminal fluid into the posterior urethra. The bladder neck closes to prevent retrograde flow.
© 2006 International Society for Sexual Medicine
The ejaculation phase is mediated through sacral 2 and 4, and involves relaxation of the external (striated) urinary sphincter, and pulsatile contraction of the bulbocavernosum and pelvic floor muscles [1,4]. The sense of “ejaculatory inevitability” occurs in response to distention of the posterior urethra [5,6]. Signals from the ejaculatory reflex center innervate the periurethral musculature, which results in pulsatile contractions (along with relaxation of the external sphincter) that propel the (seminal) fluid through the urethra [6,7]. This is typically followed by a centrally experienced orgasm; however, orgasm may or may not temporally follow the ejaculation. J Sex Med 2006;3(suppl 4):303–308
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Donatucci
Sexual interest/ Stimulation
Penile tumescence
Orgasm
Penetration
Ejaculation accompanied by orgasm
Penile detumescence
Resolution Plateau
High arousal/ penile erection
Excitement
Arousal
Desire Figure 1 Male sexual response.
The complex neurocirculatory pathway of the central control of ejaculation is dependent upon afferent sensory information and higher cortical areas. Forebrain structures involved in ejaculation include the medial preoptic area (MPOA), nucleus paragigantocellularis (nPGi), stria terminalis, amygdala, and thalamus (Figure 2). Animal studies suggest that the MPOA has a central role in augmenting copulatory behavior, as electrical stimulation of the MPOA can (i) lead to seminal emission or ejaculation in monkeys and rats; and (ii) can elicit a urethrogenital reflex in rats similar to that of human orgasm [8]. Studies in the male rat have shown that the paragigantocellular reticular nucleus (nPGi) has an inhibitory influence on ejaculation, and that the majority of descending neurons from nPGi are serotonergic [8]. There are descending serotonergic pathways from the
• Seminal emission, ejection, and orgasm are integrated into the complex pattern of copulatory behavior by several forebrain structures – Medial preoptic area (MPOA) – Nucleus paragigantocellularis (nPGi) – Stria terminalis, amygdala, and thalamus
• Multiple excitatory and inhibitory regulatory neurotransmitters – – – – – –
Serotonin Dopamine Oxytocin GABA Oxytocin Nitric oxide (NO) (maybe a reason PDE5Is have some effects)
Figure 2 Central areas for ejaculation. Adapted from Perelman MA, McMahon CG, Barada JH. Evaluation and treatment of the ejaculatory disorders. In: Lue T, ed. Atlas of male sexual dysfunction, 2004. Copyright © 2004, with permission from Current Medicine, Inc. [4]. GABA = Gammaamino-butyric acid; PVN = paraventricular nucleus.
J Sex Med 2006;3(suppl 4):303–308
nPGi to the lumbosacral motor nuclei that tonically inhibit ejaculation. Further, there are data to suggest that in addition to its stimulatory role, disinhibition of the nPGi by the MPOA results in ejaculation [8,9]. Recent findings on positron emission tomography (PET) have clearly delineated, for the first time, several regions in the human brain directly involved in ejaculation [10]. Using PET in heterosexual male volunteers who were manually stimulated by their partners, investigators measured increases in regional cerebral blood flow (rCBF) during ejaculation, as compared with sexual stimulation. They found that primary activation occurred in the mesodiencephalic transition zone, specifically the ventral tegmental area, which is associated with a broad range of “rewarding behaviors.” PET also showed “remarkably strong rCBF increases in the cerebellum.” Additional areas involved the zona incerta, subparafascicular nucleus, midbrain lateral central tegmental field ventroposterior, midline, and intralaminar thalamic nuclei. PET showed activation in the lateral putamen and adjoining areas of the claustrum, and in Brodmann areas 7/40, 18, 21, 23, and 47, only on the right side. Of note, the investigators found that contrary to data from rodent studies that suggest involvement of the MPOA, the bed nucleus of the stria terminalis, and amygdala in ejaculation, there was no increase of rCBF in any of these regions; however, reduced activation was evident in the amygdala and adjacent entorhinal cortex. The spinal cord houses the secondary ejaculatory center; however, it is not yet known how the spinal ejaculatory centers coordinate the sympathetic, parasympathetic, and motor outflow to reduce emission and expulsion. There are two different afferent pathways to the spinal cord: (i) sensory fibers of the dorsal nerve of the penis up to S4; and (ii) sympathetic fibers that transmit information to the spinal cord sympathetic ganglia [4]. Researchers have determined that sensory and cortical inputs have an important role in activating this “spinal ejaculatory generator” and its overall integration with the outflow from the sensory inputs during sexual activity [11].
Role of Neurotransmitters Norepinephrine and serotonin are among the numerous neurotransmitters involved in controlling ejaculation with secondary involvement of cholinergic, adrenergic, oxytocinergic, and Gamma-amino-butyric acid (GABA)-ergic neurons (Table 1) [1,12,13].
Etiology of Ejaculation and Pathophysiology of PE Table 1
Neurophysiology of ejaculation is very complex
• Emission controlled by sympathetic nervous system • Ejection, by the parasympathetic nervous system is greater than the sympathetic nervous system • Orgasm is a centrally controlled sensory and emotional experience • Thus, ejaculation is both cerebral and reflexive — Multiple cortical receptors and a spinal cord control centers • Cerebral receptor areas • Spinal ejaculation generator
During the emission stage of ejaculation, sympathetic signals cause the release of norepinephrine from the postganglionic neurons of the seminal tract to activate smooth muscle 1-adrenergic receptors. This leads to increased intracellular calcium levels and vas deferens smooth muscle contraction. As a result, sperm is propelled to the ampulla, which subsequently contracts, forcing the seminal fluid into the posterior urethra. Subsequently, the pudendal nerve, which originates in the S2–S4 segments of the sacral spinal cord, innervates the perineal striated muscles (including the bulbocavernosus and ishiocavernosus muscles). Pulsatile contractions of these muscles propel the seminal fluid out through the urethra in the expulsion phase of ejaculation. Expulsion is controlled by the urethromuscular reflex, whereas emission is controlled by the glans-vasal reflex [8]. The neurotransmitter and potent vasoconstrictor serotonin (5-hydroxytryptamine [5-HT]) is now understood to have an inhibitory effect on ejaculation and male sexual activity [8,14]. Serotonergic neurons are self-regulated via a negative feedback system. Serotonin is released into the synaptic cleft from presynaptic axonal vesicles; 5HT transporters bind with and remove serotonin from the synaptic cleft to prevent overstimulation of the postsynaptic receptors (Figure 3) [8,15]. Selective serotonin reuptake inhibitors (SSRIs) block 5-HT transporters, increasing synaptic cleft • 5-HT neurotransmission is locally regulated by the 5-HT transporter reuptake system • As 5-HT is released, the transporter system is activated, removing 5-HT from the synaptic cleft and preventing overstimulation of postsynaptic 5-HT receptors Figure 3 Serotonergic control of ejaculation [8]. 5-HT = 5hydroxy tryptamine.
305 serotonin, whereas 5-HT1a autoreceptors are activated to inhibit further 5-HT release. To date, numerous 5-HT receptor subtypes have been identified and associated with ejaculation, with a particular focus on 5-HT1a and 5-HT2c as they relate to sexual arousal and ejaculation [16]. The speed of ejaculation is determined by 5-HT2c and 5-HT2a receptors [13]. Injection of the selective 5-HT1a receptor agonist 8-OH-DPAT into male rats was shown to lower central serotonin levels, causing the rats to ejaculate at the first or second intromission [8,12,17]. In contrast, microinjection of an SSRI into the rat lateral hypothalamus was shown to increase central 5-HT levels and delay ejaculation [9]. In humans, the adverse event profile of the SSRI class of drugs includes delayed ejaculation and decreased libido [8,14]. Gamma-amino-butyric acid is also believed to have an inhibitory and regulatory role in sexual functioning [8]. Systemic or local administration of GABAA agonists inhibits sexual behavior; in contrast, GABAA antagonists reduce ejaculatory latency—but only when administered by microinjection directly into the MPOA [8]. Finally, nitric oxide (NO) in the MPOA has been shown to promote penile erection—and may inhibit seminal emission [8]. Data reported in 2005 by Mancina et al. show that there is phosphodiesterase type 5 (PDE5) expression, which regulates NO-induced relaxation and cyclic guanosine monophosphate (cGMP) breakdown in smooth muscle cells, on the vas deferens [18]. And, it is negatively involved in regulating NO-induced relaxation. They report that both the corpora cavernosa and the vas deferens had the same sensitivity to a broad panel of PDE inhibitors, specifically tadalafil, sildenafil, zaprinast, vinpocetine, dipyridamole, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), and cilostamide. Further, cGMPmetabolizing activity in the vas deferens was largely associated with PDE5.
The Role of Hormones In 1997, Peri et al. showed that endothelium (ET)-1 messenger ribonucleic acid and protein are readily detectable in the epithelial compartment of the human epididymis, a duct that is sensitive to estrogen and androgen [19]. Moreover, they showed that ET-converting enzyme-1 is expressed in the epididymis, which would indicate active processing of the prohormone within the epididymis. Additionally, the investigators determined two classes of ET receptors within the muscle cells of the epididymis, which were subsequently found J Sex Med 2006;3(suppl 4):303–308
306 to mediate in vitro epididymis contractile activity. They concluded that ET-1 could play a major role in sperm progression through the epididymis. More recently, Filippi et al. produced data to suggest that oxytocin receptors also mediate an estrogen-dependent increase in epididymal contractility [20]. Oxytocin receptors are also implicated in the in vitro and in vivo contractility of the penis, and are believed to play a role in maintaining penile detumescence, and postorgasmic penile flaccidity [21,22]. Pathophysiology of Premature Ejaculation
Given that the biologic mechanisms involved in ejaculation remain to be clearly identified, it is not surprising that the pathophysiology of PE is equally poorly understood, despite the fact that it is the most common sexual disorder in men. With respect to prevalence, the exact instance is not known; however, PE is generally believed to affect between 4% and 39% of men [23]. The figures on the incidence vary for a number of reasons, not the least of which is the lack of a universally accepted definition for PE. Classifications that are generally agreed upon, however, are lifelong (primary) and acquired (secondary) PE, as originally suggested by Schapiro in 1943 [9,23]. Additionally, PE is further distinguished as global or situational: global denoting its existence regardless of partner(s) or situation(s), and situational referring to the occurrence of PE only with certain partners or circumstances [24]. The difficulties and challenges inherent in defining PE are discussed elsewhere in this journal supplement; for the purposes of this article, PE is defined by three criteria: (i) a short ejaculatory latency; (ii) an inability to control ejaculation; and (iii) concern or distress about the condition. In general, an intravaginal ejaculatory latency time (IELT) under 2 minutes is suggestive of PE [8]. Historically, potential explanations for PE have involved psychological causes such as early sexual experiences, sexual conditioning, sexual technique, frequency of sexual intercourse, and anxiety [23]. In 1943, Schapiro suggested that PE results from a psychosomatic disturbance, caused by the combination of a psychologically overanxious constitution and “an inferior ejaculatory apparatus as a point of least resistance for emotional pressure” [9]. Additionally, it has been suggested that the sympathetic nervous system can be activated by anxiety which results in an earlier emission phase J Sex Med 2006;3(suppl 4):303–308
Donatucci of ejaculation, and subsequently, a reduced ejaculatory threshold [23,25,26]. Two recent studies have demonstrated a correlation between anxiety, PE, and erectile dysfunction (ED) [27,28]. In the first study, 755 patients attending an outpatient clinic for sexual dysfunction completed the Structured Interview on Erectile Dysfunction (SIEDY), a brief, recently validated, multidimensional instrument [27]. Participants also underwent complete physical examinations in addition to biochemical, hormonal, psychometric, penile vascular, and rigidometric evaluations. Investigators found that 214 (28%) participants who reported suffering from PE were younger compared with non-PE participants: 48.5 ± 12.6 vs. 52.9 ± 12.9 years, respectively; (P < 0.0001). Further, compared with the rest of the patients, they demonstrated an increased prevalence for symptoms of anxiety. Interestingly, the patients with PE had significantly lower fasting plasma glucose (94 [87–110] and 98 [89–113] mg/ dL for PE and non-PE, respectively; P < 0.01). They also demonstrated a greater capacity for partial erection, compared with those men with ED. Notably, a greater prevalence of hyperthyroidism was evident among the men with PE, which has also been noted in a recent multicenter study discussed later in this article [29]. The second study evaluated 822 consecutive patients with ED and PE. The SIEDY was used in addition to the MHQ-A scoring from Middlesex Hospital Questionnaire (MHQ) [28]. Participants underwent hormonal and metabolic testing, nocturnal penile tumescence testing, and penile Doppler ultrasound. The free-floating anxiety measures reported in the MHQ-A were significantly elevated in patients with PE and ED (P < 0.05 for both). And, there was a significant correlation between life stressors such as dissatisfaction at work or with key relationships in the family or marriage/couple.
Neurobiologic Etiologies of PE Currently, the most likely neurogenic etiology of PE has been attributed to either a hyposensitivity of 5-HT2c receptors or a hypersensitivity of the 5HT1a receptors [9,15]. It is believed that the ejaculatory threshold for men with low 5-HT levels and/or 5-HT2c receptor hyposensitivity may be genetically “set” at a lower point, resulting in a more rapid ejaculation [14]. In contrast, men with a very high setpoint may experience delayed or absent ejaculation despite prolonged sexual stimulation and despite achieving a full erection. This
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Etiology of Ejaculation and Pathophysiology of PE theory is supported by research that has demonstrated the efficacy of some SSRIs in inhibiting PE, presumably because of activation of the 5HT2c receptor which then decreases the function of the 5-HT1a receptor or restores the balance between the two receptor functions (5-HT1a and 5-HT2c) [15]. Acute administration of traditional SSRIs results in a sustained mild stimulation of all postsynaptic serotonin receptors. However, continued (chronic) administration of serotonin desensitizes the autoreceptors, ultimately increasing serotonergic neurotransmission which effects a greater degree of ejaculatory delay [16]. It has been suggested that men with PE have a hyperexcitable ejaculatory reflex, resulting in a faster emission and/or expulsion phase. In addition, it has been proposed that men with PE may have a faster bulbocavernosus reflex, impairing their ability to learn to control ejaculation [8]. One of the most well-known behavioral interventions for PE—the “squeeze technique”—presumes that PE results from a defective ejaculatory reflex [30]. Nevertheless, research examining this etiology was plagued by poor methodology or contradictory results. More recent data show a significantly higher rate of prostatic inflammation or infection among men diagnosed with PE than controls (P < 0.05) [31]. Prostatic pathologies have therefore been suggested as a possible etiology of PE [32]. Significantly higher fasting serum leptin levels have also been implicated in PE. A study conducted in 15 individuals diagnosed with PE vs. 15 healthy controls showed a negative correlation between IELT and leptin levels in both groups [33]. There is also evidence for an association between hyperthyroidism and PE [27]. A recent multicenter Italian study demonstrated a 50% incidence of PE in the men with hyperthyroidism and a 7.1% incidence in men with hypothyroidism [29]. Once thyroid hormone levels were normalized, the incidence of PE fell from 50% to 15%. Furthermore, men with hyperthyroidism experienced a doubling of ejaculatory latency time following treatment, from 2.4 ± 2.1 to 4.0 ± 2.0 minutes (P < 0.01) while men with hypothyroidism experienced a decrease, 21.8 ± 10.9 to 7.4 ± 7.2 minutes (P < 0.01). Finally, limited information supports the possibility of a genetic predisposition to PE. Schapiro first noted a familial predisposition in 1947; a more recent study by Waldinger found that 10 of 14 first-degree male relatives of men with lifelong PE also had PE (defined as IELT < 1 minute) [34,35].
Taken overall, the roles of neurobiological and psychogenic factors discussed in this article warrant additional investigation. While the body of evidence as it currently exists has undoubtedly moved the field of male sexual medicine forward, it has, not surprisingly, raised many more questions that must be addressed if the pathophysiologies of male sexual disorders such as PE are to be fully understood. Further research will also hopefully lead to improved treatments and provide clinicians with more comprehensive clinical management strategies. Summary
While research continues to better define the etiology of PE, best available evidence would suggest that the pathophysiology appears to be both neurobiogenic and psychogenic. Further, this appears to be true for both lifelong and acquired PE. While psychogenic factors, specifically anxiety, appear to be contributory to PE, pharmacologic intervention of PE can modify IELT, which suggests that IELT is a biological variable, and is likely biologically dependent upon neurotransmitters and hormones [23]. During the coming years, research will no doubt move the understanding and treatment of PE forward, and, enable a well-informed definition of the condition to be established. Corresponding Author: Craig F. Donatucci, MD, Division of Urology, Duke University Medical Center, Trent Drive, Durham, NC 27710, USA. Tel: 919-6842127; Fax: 919-684-7423; E-mail: [email protected]. edu Conflict of Interest: None declared. References
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308 5 McMahon C, Samali R. Pharmacological treatment of premature ejaculation. Curr Opin Urol 1999;9:553–61. 6 Shenassa B, Hellstrom W. Understanding ejaculatory disorders. Contemp Urol 2001;13:51–9. 7 Witt MA, Grantmyre JE. Ejaculatory failure. World J Urol 1993;11:89–95. 8 McMahon C, Meston C, Abdo C, Hull E, Incrocci L, Levin R, Perelman M, Rowland D, Sipski M, Stuckey B, Waldinger M, Xin ZC. of the Committee 9B. Disorders of orgasm in men and women, ejaculatory disorders in men. 2004. 9 Waldinger MD. The neurobiological approach to premature ejaculation. J Urol 2002;168:2359–67. 10 Holstege G, Georgiadis J, Paans A, Meiners L, van der Graaf F, Reinders A. Brain activation during human male ejaculation. J Neurosci 2003;23:9185– 93. 11 Coolen L, Allard J, Truitt W, McKenna K. Central regulation of ejaculation. Physiol Behav 2004; 83:203–15. 12 Ahlenius S, Larsson K, Svensson L, Hjorth S, Carlsson A. Effects of a new type of 5-HT receptor agonist on male rat sexual behavior. Pharm Biochem Behav 1981;15:785–92. 13 McMahon C, Abdo C, Incrocci L, Perelman M, Rowland D, Waldinger M, Xin ZC. Disorders of orgasm and ejaculation in men. J Sex Med 2004;1:58–65. 14 Waldinger M, Olivier B. Selective serotonin reuptake inhibitor-induced sexual dysfunction: Clinical and research considerations. Int Clin Psychopharmacol 1998;13(suppl 6):S27–33. 15 Waldinger M, Berendsen H, Blok B, Olivier B, Holstege G. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: The involvement of the serotonergic system. Behav Brain Res 1998;92:111–8. 16 Waldinger M, Olivier B. Utility of selective serotonin reuptake inhibitors in premature ejaculation. Curr Opin Invest Drugs 2004;5:743–7. 17 Haensel S, Mos J, Oliver B, Slob K. Sex behavior of male and female wistar rats affected by the serotonin agonist 8-OH-DPAT. Pharmacol Biochem Behav 1991;40:221–8. 18 Mancina R, Filippi S, Marini M, Morelli A, Vignozzi L, Salonia A, Montorsi F, Mondaini N, Vannelli GB, Donati S, Lotti F, Forti G, Maggi M. Expression and functional activity of phosphodiesterase type 5 in human and rabbit vas deferens. Mol Hum Reprod 2005;11:107–15. 19 Alessandro P, Fantoni G, Granchi S, Vannelli GB, Barni T, Amerini T, Pupilli C, Barbagli G, Forti G, Serio M, Maggi M. Gene expression of Endothelin-1, Endothelin-Converting Enzyme-1, and endothelin receptors in human epididymis. J Clin Endocrinol Metab 1997;82:3797–806. 20 Filippi S, Morelli A, Vignozzi L, Vannelli GB, Marini M, Ferruzzi P, Mancina R, Crescioli C, J Sex Med 2006;3(suppl 4):303–308
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Mondaini N, Forti G, Ledda F, Maggi M. Oxytocin mediates the estrogen-dependent contractile activity of endothelin-1 in human and rabbit epididymis. Endocrinology 2005;146:3506–17. Vignozzi L, Filippi S, Luconi M, Morelli A, Mancina R, Marini M, Vannelli GB, Granchi S, Orlando C, Gelmini S, Ledda F, Forti G, Maggi M. Oxytocin receptor is expressed in the penis and mediates an estrogen-dependent smooth muscle contractility. Endocrinology 2004;145:1823–34. Zhang X, Filippi S, Vignozzi L, Morelli A, Mancina R, Luconi M, Donati S, Marini M, Vannelli GB, Forti G, Maggi M. Identification, localization and functional in vitro and in vivo activity of oxytocin receptor in the rat penis. J Endocrinol 2005; 184:567–76. McMahon C. AUA Update Series 2005. Lesson 34, Vol. 24. AUA Education and Research Inc; 2005. Ibrahim A-H. Phosphodiesterase 5 inhibitors in rapid ejaculation: Potential use and possible mechanisms of action. Drugs 2004;64:13–26. Kaplan H, Kohl R, Pomeroy W, Offit A, Hogan B. Group treatment of premature ejaculation. Arch Sex Behav 1974;3:443–52. Williams W. Secondary premature ejaculation. Aust NZ J Psychiatry 1984;18:333–40. Corona G, Petrone L, Mannucci E, Jannini EA, Mansani R, Magini A, Giommi R, Forti G, Maggi M. Psycho-biological correlates of rapid ejaculation in patients attending an andrologic unit for sexual dysfunctions. Eur Urol 2004;46:615–22. Corona G, Mannucci E, Petrone L, Ricca V, Balercia G, Giommi R, Forti G, Maggi M. Psychobiological correlates of free-floating anxiety symptoms in male patients with sexual dysfunctions. J Androl 2006;27:86–93. Carani C, Isidori A, Granata A, Carosa E, Maggi M, Lenzi A, Jannini EA. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab 2005;90:6472–9. Semans JH. Premature ejaculation: A new approach. South Med J 1956;49:353–8. Screponi E, Carosa E, Di Stasi S, Pepe M, Carruba G, Jannini E. Prevalence of chronic prostatitis in men with premature ejaculation. Urology 2001; 58:198–202. Jannini E, Simonelli C, Lenzi A. Disorders of ejaculation. J Endocrinol Invest 2002;25:1006–19. Atmaca M, Kuloglu M, Tezcan E, Semercioz A, Ustundag B, Ayar A. Serum leptin levels in patients with premature ejaculation. Arch Androl 2002; 48:345–50. Schapiro B. Premature ejaculation. A review of 1,130 cases. J Urol 1943;50:374–9. Waldinger MD, Rietschel M, Nothen MM, Hengeveld MW, Olivier B. Familial occurrence of primary premature ejaculation. Psychiatr Genet 1998;8:37–40.
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Etiology of Ejaculation and Pathophysiology of Premature Ejaculation Craig F. Donatucci, MD Division of Urology, Duke University Medical Center, Durham, NC, USA DOI: 10.1111/j.1743-6109.2006.00305.x
ABSTRACT
Introduction. Ejaculation is comprised of three stages of the male sexual response cycle, namely emission, ejection, and orgasm; however, in comparison with erection, which is a well-understood component of male sexual response, the pathophysiology of ejaculation has yet to be fully delineated. Premature ejaculation (PE), the most common sexual disorder in men, while believed to have a multifactorial etiology, is even less well understood. Aim. This article reviews the physiology of ejaculation, and the multifactorial pathophysiology of PE. Methods. The Sexual Medicine Society of North America hosted a State of the Art Conference on Premature Ejaculation on June 24–26, 2005 in collaboration with the University of South Florida. The purpose was to have an open exchange of contemporary research and clinical information on PE. There were 16 invited presenters and discussants; the group focused on several educational objectives. Main Outcome Measure. Data were obtained by extensive examination of published peer-reviewed literature. Results. Evidence supports that biologic mechanisms associated with neurotransmitters such as norepinephrine, serotonin, oxytocin, Gamma-amino-butyric acid, and nitric oxide (NO) as well as the hormone estrogen play central roles in ejaculation, and subsequently may mediate PE. There is also emerging evidence to show that hyperthyroidism may be a causal factor in PE. Recent data also suggest that psychogenic factors include high level of any experience by some men with PE. Conclusions. The pathophysiology of both lifelong and acquired PE appears to be both neurobiogenic and psychogenic. While psychogenic factors appear to be contributory to PE, pharmacologic intervention of PE can modify intravaginal ejaculatory latency time (IELT), which suggests that IELT is a biological variable, and is likely biologically dependent upon neurotransmitters and hormones. Donatucci CF. Etiology of ejaculation and pathophysiology of premature ejaculation. J Sex Med 2006;3(suppl 4):303–308. Key Words. History of Sexual Dysfunction; Premature Ejaculation; Epidemiology
The Physiology of Ejaculation
A
lthough ejaculation has traditionally been thought of as a single event, in fact, it comprises three separate and distinct components: emission, ejection, and orgasm. Further, they involve separate neural pathways [1] (Figure 1). Antegrade ejaculation begins with emission, which is a sympathetically mediated (thoracic 10 to lumbar 2) neural function that acts through alpha-adrenergic receptors [2,3]. Emission leads to the contraction of seminal vesicles and the prostate with expulsion of sperm and seminal fluid into the posterior urethra. The bladder neck closes to prevent retrograde flow.
© 2006 International Society for Sexual Medicine
The ejaculation phase is mediated through sacral 2 and 4, and involves relaxation of the external (striated) urinary sphincter, and pulsatile contraction of the bulbocavernosum and pelvic floor muscles [1,4]. The sense of “ejaculatory inevitability” occurs in response to distention of the posterior urethra [5,6]. Signals from the ejaculatory reflex center innervate the periurethral musculature, which results in pulsatile contractions (along with relaxation of the external sphincter) that propel the (seminal) fluid through the urethra [6,7]. This is typically followed by a centrally experienced orgasm; however, orgasm may or may not temporally follow the ejaculation. J Sex Med 2006;3(suppl 4):303–308
304
Donatucci
Sexual interest/ Stimulation
Penile tumescence
Orgasm
Penetration
Ejaculation accompanied by orgasm
Penile detumescence
Resolution Plateau
High arousal/ penile erection
Excitement
Arousal
Desire Figure 1 Male sexual response.
The complex neurocirculatory pathway of the central control of ejaculation is dependent upon afferent sensory information and higher cortical areas. Forebrain structures involved in ejaculation include the medial preoptic area (MPOA), nucleus paragigantocellularis (nPGi), stria terminalis, amygdala, and thalamus (Figure 2). Animal studies suggest that the MPOA has a central role in augmenting copulatory behavior, as electrical stimulation of the MPOA can (i) lead to seminal emission or ejaculation in monkeys and rats; and (ii) can elicit a urethrogenital reflex in rats similar to that of human orgasm [8]. Studies in the male rat have shown that the paragigantocellular reticular nucleus (nPGi) has an inhibitory influence on ejaculation, and that the majority of descending neurons from nPGi are serotonergic [8]. There are descending serotonergic pathways from the
• Seminal emission, ejection, and orgasm are integrated into the complex pattern of copulatory behavior by several forebrain structures – Medial preoptic area (MPOA) – Nucleus paragigantocellularis (nPGi) – Stria terminalis, amygdala, and thalamus
• Multiple excitatory and inhibitory regulatory neurotransmitters – – – – – –
Serotonin Dopamine Oxytocin GABA Oxytocin Nitric oxide (NO) (maybe a reason PDE5Is have some effects)
Figure 2 Central areas for ejaculation. Adapted from Perelman MA, McMahon CG, Barada JH. Evaluation and treatment of the ejaculatory disorders. In: Lue T, ed. Atlas of male sexual dysfunction, 2004. Copyright © 2004, with permission from Current Medicine, Inc. [4]. GABA = Gammaamino-butyric acid; PVN = paraventricular nucleus.
J Sex Med 2006;3(suppl 4):303–308
nPGi to the lumbosacral motor nuclei that tonically inhibit ejaculation. Further, there are data to suggest that in addition to its stimulatory role, disinhibition of the nPGi by the MPOA results in ejaculation [8,9]. Recent findings on positron emission tomography (PET) have clearly delineated, for the first time, several regions in the human brain directly involved in ejaculation [10]. Using PET in heterosexual male volunteers who were manually stimulated by their partners, investigators measured increases in regional cerebral blood flow (rCBF) during ejaculation, as compared with sexual stimulation. They found that primary activation occurred in the mesodiencephalic transition zone, specifically the ventral tegmental area, which is associated with a broad range of “rewarding behaviors.” PET also showed “remarkably strong rCBF increases in the cerebellum.” Additional areas involved the zona incerta, subparafascicular nucleus, midbrain lateral central tegmental field ventroposterior, midline, and intralaminar thalamic nuclei. PET showed activation in the lateral putamen and adjoining areas of the claustrum, and in Brodmann areas 7/40, 18, 21, 23, and 47, only on the right side. Of note, the investigators found that contrary to data from rodent studies that suggest involvement of the MPOA, the bed nucleus of the stria terminalis, and amygdala in ejaculation, there was no increase of rCBF in any of these regions; however, reduced activation was evident in the amygdala and adjacent entorhinal cortex. The spinal cord houses the secondary ejaculatory center; however, it is not yet known how the spinal ejaculatory centers coordinate the sympathetic, parasympathetic, and motor outflow to reduce emission and expulsion. There are two different afferent pathways to the spinal cord: (i) sensory fibers of the dorsal nerve of the penis up to S4; and (ii) sympathetic fibers that transmit information to the spinal cord sympathetic ganglia [4]. Researchers have determined that sensory and cortical inputs have an important role in activating this “spinal ejaculatory generator” and its overall integration with the outflow from the sensory inputs during sexual activity [11].
Role of Neurotransmitters Norepinephrine and serotonin are among the numerous neurotransmitters involved in controlling ejaculation with secondary involvement of cholinergic, adrenergic, oxytocinergic, and Gamma-amino-butyric acid (GABA)-ergic neurons (Table 1) [1,12,13].
Etiology of Ejaculation and Pathophysiology of PE Table 1
Neurophysiology of ejaculation is very complex
• Emission controlled by sympathetic nervous system • Ejection, by the parasympathetic nervous system is greater than the sympathetic nervous system • Orgasm is a centrally controlled sensory and emotional experience • Thus, ejaculation is both cerebral and reflexive — Multiple cortical receptors and a spinal cord control centers • Cerebral receptor areas • Spinal ejaculation generator
During the emission stage of ejaculation, sympathetic signals cause the release of norepinephrine from the postganglionic neurons of the seminal tract to activate smooth muscle 1-adrenergic receptors. This leads to increased intracellular calcium levels and vas deferens smooth muscle contraction. As a result, sperm is propelled to the ampulla, which subsequently contracts, forcing the seminal fluid into the posterior urethra. Subsequently, the pudendal nerve, which originates in the S2–S4 segments of the sacral spinal cord, innervates the perineal striated muscles (including the bulbocavernosus and ishiocavernosus muscles). Pulsatile contractions of these muscles propel the seminal fluid out through the urethra in the expulsion phase of ejaculation. Expulsion is controlled by the urethromuscular reflex, whereas emission is controlled by the glans-vasal reflex [8]. The neurotransmitter and potent vasoconstrictor serotonin (5-hydroxytryptamine [5-HT]) is now understood to have an inhibitory effect on ejaculation and male sexual activity [8,14]. Serotonergic neurons are self-regulated via a negative feedback system. Serotonin is released into the synaptic cleft from presynaptic axonal vesicles; 5HT transporters bind with and remove serotonin from the synaptic cleft to prevent overstimulation of the postsynaptic receptors (Figure 3) [8,15]. Selective serotonin reuptake inhibitors (SSRIs) block 5-HT transporters, increasing synaptic cleft • 5-HT neurotransmission is locally regulated by the 5-HT transporter reuptake system • As 5-HT is released, the transporter system is activated, removing 5-HT from the synaptic cleft and preventing overstimulation of postsynaptic 5-HT receptors Figure 3 Serotonergic control of ejaculation [8]. 5-HT = 5hydroxy tryptamine.
305 serotonin, whereas 5-HT1a autoreceptors are activated to inhibit further 5-HT release. To date, numerous 5-HT receptor subtypes have been identified and associated with ejaculation, with a particular focus on 5-HT1a and 5-HT2c as they relate to sexual arousal and ejaculation [16]. The speed of ejaculation is determined by 5-HT2c and 5-HT2a receptors [13]. Injection of the selective 5-HT1a receptor agonist 8-OH-DPAT into male rats was shown to lower central serotonin levels, causing the rats to ejaculate at the first or second intromission [8,12,17]. In contrast, microinjection of an SSRI into the rat lateral hypothalamus was shown to increase central 5-HT levels and delay ejaculation [9]. In humans, the adverse event profile of the SSRI class of drugs includes delayed ejaculation and decreased libido [8,14]. Gamma-amino-butyric acid is also believed to have an inhibitory and regulatory role in sexual functioning [8]. Systemic or local administration of GABAA agonists inhibits sexual behavior; in contrast, GABAA antagonists reduce ejaculatory latency—but only when administered by microinjection directly into the MPOA [8]. Finally, nitric oxide (NO) in the MPOA has been shown to promote penile erection—and may inhibit seminal emission [8]. Data reported in 2005 by Mancina et al. show that there is phosphodiesterase type 5 (PDE5) expression, which regulates NO-induced relaxation and cyclic guanosine monophosphate (cGMP) breakdown in smooth muscle cells, on the vas deferens [18]. And, it is negatively involved in regulating NO-induced relaxation. They report that both the corpora cavernosa and the vas deferens had the same sensitivity to a broad panel of PDE inhibitors, specifically tadalafil, sildenafil, zaprinast, vinpocetine, dipyridamole, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), and cilostamide. Further, cGMPmetabolizing activity in the vas deferens was largely associated with PDE5.
The Role of Hormones In 1997, Peri et al. showed that endothelium (ET)-1 messenger ribonucleic acid and protein are readily detectable in the epithelial compartment of the human epididymis, a duct that is sensitive to estrogen and androgen [19]. Moreover, they showed that ET-converting enzyme-1 is expressed in the epididymis, which would indicate active processing of the prohormone within the epididymis. Additionally, the investigators determined two classes of ET receptors within the muscle cells of the epididymis, which were subsequently found J Sex Med 2006;3(suppl 4):303–308
306 to mediate in vitro epididymis contractile activity. They concluded that ET-1 could play a major role in sperm progression through the epididymis. More recently, Filippi et al. produced data to suggest that oxytocin receptors also mediate an estrogen-dependent increase in epididymal contractility [20]. Oxytocin receptors are also implicated in the in vitro and in vivo contractility of the penis, and are believed to play a role in maintaining penile detumescence, and postorgasmic penile flaccidity [21,22]. Pathophysiology of Premature Ejaculation
Given that the biologic mechanisms involved in ejaculation remain to be clearly identified, it is not surprising that the pathophysiology of PE is equally poorly understood, despite the fact that it is the most common sexual disorder in men. With respect to prevalence, the exact instance is not known; however, PE is generally believed to affect between 4% and 39% of men [23]. The figures on the incidence vary for a number of reasons, not the least of which is the lack of a universally accepted definition for PE. Classifications that are generally agreed upon, however, are lifelong (primary) and acquired (secondary) PE, as originally suggested by Schapiro in 1943 [9,23]. Additionally, PE is further distinguished as global or situational: global denoting its existence regardless of partner(s) or situation(s), and situational referring to the occurrence of PE only with certain partners or circumstances [24]. The difficulties and challenges inherent in defining PE are discussed elsewhere in this journal supplement; for the purposes of this article, PE is defined by three criteria: (i) a short ejaculatory latency; (ii) an inability to control ejaculation; and (iii) concern or distress about the condition. In general, an intravaginal ejaculatory latency time (IELT) under 2 minutes is suggestive of PE [8]. Historically, potential explanations for PE have involved psychological causes such as early sexual experiences, sexual conditioning, sexual technique, frequency of sexual intercourse, and anxiety [23]. In 1943, Schapiro suggested that PE results from a psychosomatic disturbance, caused by the combination of a psychologically overanxious constitution and “an inferior ejaculatory apparatus as a point of least resistance for emotional pressure” [9]. Additionally, it has been suggested that the sympathetic nervous system can be activated by anxiety which results in an earlier emission phase J Sex Med 2006;3(suppl 4):303–308
Donatucci of ejaculation, and subsequently, a reduced ejaculatory threshold [23,25,26]. Two recent studies have demonstrated a correlation between anxiety, PE, and erectile dysfunction (ED) [27,28]. In the first study, 755 patients attending an outpatient clinic for sexual dysfunction completed the Structured Interview on Erectile Dysfunction (SIEDY), a brief, recently validated, multidimensional instrument [27]. Participants also underwent complete physical examinations in addition to biochemical, hormonal, psychometric, penile vascular, and rigidometric evaluations. Investigators found that 214 (28%) participants who reported suffering from PE were younger compared with non-PE participants: 48.5 ± 12.6 vs. 52.9 ± 12.9 years, respectively; (P < 0.0001). Further, compared with the rest of the patients, they demonstrated an increased prevalence for symptoms of anxiety. Interestingly, the patients with PE had significantly lower fasting plasma glucose (94 [87–110] and 98 [89–113] mg/ dL for PE and non-PE, respectively; P < 0.01). They also demonstrated a greater capacity for partial erection, compared with those men with ED. Notably, a greater prevalence of hyperthyroidism was evident among the men with PE, which has also been noted in a recent multicenter study discussed later in this article [29]. The second study evaluated 822 consecutive patients with ED and PE. The SIEDY was used in addition to the MHQ-A scoring from Middlesex Hospital Questionnaire (MHQ) [28]. Participants underwent hormonal and metabolic testing, nocturnal penile tumescence testing, and penile Doppler ultrasound. The free-floating anxiety measures reported in the MHQ-A were significantly elevated in patients with PE and ED (P < 0.05 for both). And, there was a significant correlation between life stressors such as dissatisfaction at work or with key relationships in the family or marriage/couple.
Neurobiologic Etiologies of PE Currently, the most likely neurogenic etiology of PE has been attributed to either a hyposensitivity of 5-HT2c receptors or a hypersensitivity of the 5HT1a receptors [9,15]. It is believed that the ejaculatory threshold for men with low 5-HT levels and/or 5-HT2c receptor hyposensitivity may be genetically “set” at a lower point, resulting in a more rapid ejaculation [14]. In contrast, men with a very high setpoint may experience delayed or absent ejaculation despite prolonged sexual stimulation and despite achieving a full erection. This
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Etiology of Ejaculation and Pathophysiology of PE theory is supported by research that has demonstrated the efficacy of some SSRIs in inhibiting PE, presumably because of activation of the 5HT2c receptor which then decreases the function of the 5-HT1a receptor or restores the balance between the two receptor functions (5-HT1a and 5-HT2c) [15]. Acute administration of traditional SSRIs results in a sustained mild stimulation of all postsynaptic serotonin receptors. However, continued (chronic) administration of serotonin desensitizes the autoreceptors, ultimately increasing serotonergic neurotransmission which effects a greater degree of ejaculatory delay [16]. It has been suggested that men with PE have a hyperexcitable ejaculatory reflex, resulting in a faster emission and/or expulsion phase. In addition, it has been proposed that men with PE may have a faster bulbocavernosus reflex, impairing their ability to learn to control ejaculation [8]. One of the most well-known behavioral interventions for PE—the “squeeze technique”—presumes that PE results from a defective ejaculatory reflex [30]. Nevertheless, research examining this etiology was plagued by poor methodology or contradictory results. More recent data show a significantly higher rate of prostatic inflammation or infection among men diagnosed with PE than controls (P < 0.05) [31]. Prostatic pathologies have therefore been suggested as a possible etiology of PE [32]. Significantly higher fasting serum leptin levels have also been implicated in PE. A study conducted in 15 individuals diagnosed with PE vs. 15 healthy controls showed a negative correlation between IELT and leptin levels in both groups [33]. There is also evidence for an association between hyperthyroidism and PE [27]. A recent multicenter Italian study demonstrated a 50% incidence of PE in the men with hyperthyroidism and a 7.1% incidence in men with hypothyroidism [29]. Once thyroid hormone levels were normalized, the incidence of PE fell from 50% to 15%. Furthermore, men with hyperthyroidism experienced a doubling of ejaculatory latency time following treatment, from 2.4 ± 2.1 to 4.0 ± 2.0 minutes (P < 0.01) while men with hypothyroidism experienced a decrease, 21.8 ± 10.9 to 7.4 ± 7.2 minutes (P < 0.01). Finally, limited information supports the possibility of a genetic predisposition to PE. Schapiro first noted a familial predisposition in 1947; a more recent study by Waldinger found that 10 of 14 first-degree male relatives of men with lifelong PE also had PE (defined as IELT < 1 minute) [34,35].
Taken overall, the roles of neurobiological and psychogenic factors discussed in this article warrant additional investigation. While the body of evidence as it currently exists has undoubtedly moved the field of male sexual medicine forward, it has, not surprisingly, raised many more questions that must be addressed if the pathophysiologies of male sexual disorders such as PE are to be fully understood. Further research will also hopefully lead to improved treatments and provide clinicians with more comprehensive clinical management strategies. Summary
While research continues to better define the etiology of PE, best available evidence would suggest that the pathophysiology appears to be both neurobiogenic and psychogenic. Further, this appears to be true for both lifelong and acquired PE. While psychogenic factors, specifically anxiety, appear to be contributory to PE, pharmacologic intervention of PE can modify IELT, which suggests that IELT is a biological variable, and is likely biologically dependent upon neurotransmitters and hormones [23]. During the coming years, research will no doubt move the understanding and treatment of PE forward, and, enable a well-informed definition of the condition to be established. Corresponding Author: Craig F. Donatucci, MD, Division of Urology, Duke University Medical Center, Trent Drive, Durham, NC 27710, USA. Tel: 919-6842127; Fax: 919-684-7423; E-mail: [email protected]. edu Conflict of Interest: None declared. References
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