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C O Premature N T I N Timothy G. Schuster U I N G remature ejaculation (PE) is a common entity that can have a significant is one of the most com- impact on an individual’s sexual satisfaction and quality of life. Both mon complaints of men behavioral and pharmacological options are available and effective E or couples presenting for men presenting with this condition. D Pwith ejaculatory disorders. Other common names for this entity U include early or rapid ejacula- Anatomy contracts prior to seminal emis- C tion. Similar to erectile dysfunc- To better understand ejacula- sion to create an enclosed pres- A tion, PE is not life threatening but tory disorders, a review of the sure chamber in the prostatic T may have a significant impact on urethra. Normally this sphincter relevant anatomy and physiology I a patient’s and his partner’s qual- is important. The fluid in the relaxes at the appropriate time to ity of life and sexual satisfaction. ejaculate arises from the seminal allow for antegrade ejaculation. O Additionally, PE can affect men vesicles, prostate, and urethral Neurologically, the ejaculato- N across all age ranges making this glands. The prostate is formed ry process is under both central entity the most common male from epithelial outgrowths of the and peripheral nervous system sexual disorder. pelvic urethra during the 8th week control. The cutaneous nerves of the penis are involved in the Definition of development. Approximately 4 weeks later, the mesonephric local stimulus of the ejaculatory Despite its prevalence, there is (Wolffian) ducts fuse with the process. Stimulatory impulses no consensus on the definition of ipsilateral rete tubules to form are transmitted through the PE. Some authors have suggested the epididymis and vas deferens pudendal nerve to the spinal that PE exists when the man (Park, 2002). Distally, outpouch- cord. Although the specific loca- reaches within 1 minute of ing of the mesonephric ducts tion of the centrally located ejac- vaginal penetration (Waldinger, form the seminal vesicles. A sep- ulatory center has not been fully Hengeveld, Zwinderman, & tum divides this outgrowth into elucidated, the hypothalamus Olivier, 1998). Others have advo- ejaculatory ducts at the ampulla seems to play an integral part cated not defining the disorder of the vas in the prostatic urethra. (Coolen, Allard, Truitt, & with a specific time duration and The bladder neck lies proxi- McKenna, 2004; Herberg, 1963; instead suggest that a diagnosis is mal to the paired ejaculatory Thomas, 1983). Within the cen- made when the man ejaculates too ducts and acts as a physiologic tral nervous system, serotonin early for female partner satisfac- sphincter during the ejaculatory appears to be inhibitory while tion in greater than one-half of process. The smooth muscle sur- dopamine acts as an excitatory encounters (Masters & Johnson, rounding the urethra in this area agent (Kimura, Kisaki, Sakurada, 1970). The American Urological is under autonomic control and, & Tadano, 1976; 1977). Association (AUA) proposed a under normal circumstances, Nerves responsible for the definition of “ejaculation that contracts during ejaculation ejaculatory process travel from occurs sooner than desired, which prevents retrograde flow the cerebral cortex to the thora- either before or shortly after pen- of from occurring. Distal columbar and sympathetic etration, causing distress to to the ejaculatory ducts and veru- chains at T10-L3 (Thomas, 1983). either one or both partners” montanum lies the external ure- Post-synaptic adrenergic fibers (AUA Consensus Panel, 2004). thral sphincter. This sphincter then course through the superior consists of a central muscle layer hypogastric plexus located at the Timothy G. Schuster, MD, is an under autonomic control sur- aortic bifurcation prior to dis- Assistant Professor or , the rounded by a muscular layer persing laterally near the bladder Department of Urology, the University under somatic control. It also and to their end organs of Michigan, Ann Arbor, MI. Ja ua y 006 e o 050 0 3 © UROLOGIC NURSING / August 2006 / Volume 26 Number 4 245 UNJ August 2006-246.ps 7/24/06 3:08 PM Page 246

C which include the epididymis, responsible for the projectile have had the disorder present O vas deferens, seminal vesicles, phase of ejaculation are skeletal since . Those with sec- prostate, and bladder neck. muscles normally under volun- ondary or acquired PE have an N Expulsion of seminal fluid from tary control, all events of the onset later in life. T the posterior urethra is stimulat- ejaculatory process are involun- I ed through activation of nerve tary once the reflex is initiated. Evaluation fibers within the pudendal nerve The ejaculatory process nor- When men present with PE, N originating from S2-S4. mally occurs during sexual activ- a thorough sexual history is para- U ity during which genital sensory mount to the evaluation. It is I Physiological Events input is coordinated with erotic important to distinguish the Of Ejaculation imagery from the cerebral cortex. presence of PE from erectile dys- N The ejaculatory process con- While it is known that input from function as some men will con- G sists of the coordinated activity the cortex augments sensory fuse the two entities. Patients of deposition of seminal fluid stimulation, the ejaculatory should be questioned regarding E into the posterior urethra with reflex can be activated from cere- the duration of symptoms (life- subsequent antegrade expulsion. bral input alone as evidenced by long vs. acquired) as well as the D Three distinct physiological nocturnal emission. frequency. If the PE is acquired, it U phases of the ejaculatory process is important to explore the tim- Premature Ejaculation C have been described as bladder ing or events surrounding when neck contraction, emission, and Despite its widespread pre- the PE began and if it is situa- A ejaculation. Detailed evaluation valence, the etiology of PE is not tional and/or with specific part- T of the ejaculatory process has agreed upon. For many years PE ners. In all men, one should also I been evaluated using transrectal was considered a neurosis as a inquire about the nature of the ultrasound (Gil-Vernet, Alvarez- result of unconscious conflict sexual encounters in regards to O Vijande, Gil-Vernet, & Gil-Vernet, (Waldinger, 2002). Subsequent to durations of , sexual N 1994), fluoroscopy (Mitsuya, Asai, this, many researchers attributed intercourse, and . Suyama, Ushida, & Hosoe, 1960; the symptoms to a learned behav- The time to ejaculation should be Sonksen, Ohl, & Wedemeyer, ior as a result of performance ascertained with sexual stimula- 2001), electromyography studies anxiety (Masters & Johnson, tion (before or after intromis- (Gerstenberg, Levin, & Wagner, 1970). More recent literature sion), as well as the degree of vol- 1990), and transurethral pressure emphasized neurobiology as the untary control over ejaculation catheters (Bohlen, Hugonnet, cause with pharmacotherapy for that the patient experiences. One Mills, Weise, & Schmid, 2000). treatment. should also try to obtain a gener- From these studies it is clear that Some research showed a al sense of the patient’s knowl- ejaculatory events occur in a sys- decreased vibratory threshold on edge about ejaculation. Some tematic fashion. the penile shaft and glans in men do not understand that the During emission, the smooth patients with PE when compared normal physiologic response is muscles in the prostate, seminal to normal controls (Xin et al., loss of after ejaculation. vesicles, and vas deferens under- 1996). Still other researchers Additionally, the degree of both- go rhythmic contractions that have demonstrated significant er that the patient and his partner result in seminal fluid being differences in sacral and cortical have from the PE should be deposited into the posterior ure- somatosensory evoked potentials obtained. In general, no further thra. Simultaneously, the bladder in patients with PE compared to testing is needed prior to initiat- neck contracts to prevent retro- controls, suggesting an underly- ing treatment. grade flow of seminal fluid into ing neurological difference the bladder (Bohlen et al., 2000). (Colpi, Fanciullacci, Beretta, Treatment Once the seminal fluid is Negri, & Zanollo, 1986; Because the etiology of PE is deposited into the posterior ure- Fanciullacci, Colpi, Beretta, & disputed, treatment options thra, the external urethral Zanollo, 1988). A more recent include behavioral, psychologi- sphincter relaxes while the peri- study suggested that a delay in cal, and attempts to alter the sen- urethral skeletal muscles rhyth- processing sensory stimuli in the sory input or retard the ejaculato- mically contract resulting in pul- central nervous system may be ry reflex through pharmacologic satile expulsion of the semen responsible for PE (Ozcan et al., means. It is important to review from the urethra. This portion of 2001). all available treatment options the ejaculatory process is stimu- Premature ejaculation has and side effects with the patient lated by branches of the puden- been classified into subtypes: pri- and preferably with his spouse as dal nerve that originate from S2- mary or secondary (Godpodinoff, well so that an informed decision S4. Although the muscles 1989). Patients with primary PE can be made.

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Sex therapy. Because of the the cream. It is important to effect. The most common side C belief by some researchers that inform patients that the cream effects of clomipramine include O PE is due to a learned behavior should be wiped off completely dry mouth and fatigue which are because of performance anxiety, prior to intercourse to prevent due to the anticholinergic prop- N became the mainstay vaginal numbness (Sahin & erties of the medication and T of treatment for many years and Bircan, 1996). appear to be dose related. I is still one option for treating PE An alternative topical agent, Given the inhibitory effects today. Acquired or situational PE SS cream, is available currently in of serotonin on the central ejacu- N is believed by many to have a Korea. It is a natural agent derived latory reflex, the efficacy of selec- U psychological basis and most from nine products. In a double- tive serotonin reuptake in- I clinicians recommend counsel- blind, randomized, placebo-con- hibitors (SSRIs) in the treatment ing at least as part of the treat- trolled Phase III trial, men with of PE is not surprising. These N ment recommendations. primary PE had a significant inhibitors in G The most common form of improvement in ejaculatory laten- multiple placebo-controlled ran- sex therapy is the “squeeze tech- cy when using SS cream when domized studies (Biri et al., E nique” during which the patient compared to controls (Choi et al., 1998; Haensel, Klem, Hop, & Slob, and/or his partner squeeze the 2000). 1998; Kara et al., 1996; Kim & Seo, D erect penile shaft before the ejac- Pharmacologic therapy. Treat- 1998; Waldinger, Hengevald, & U ulatory reflex is stimulated. ment of PE may be effective with Zwinderman, 1994; Waldinger et C Using this technique, the patient the use of several different classes al., 1998) and is the most common will learn to voluntarily delay of medications. Currently no med- class of medications used to treat A ejaculation while maintaining ication is Food and Drug PE currently. Dosing of the vari- T sexual excitation (Masters & Administration (FDA) approved ous SSRIs for the treatment of PE I Johnson, 1970). While this tech- for treating PE. Despite this, sever- include fluoxetine (20 to 40 nique can have significant al medications are routinely pre- mg/day), sertraline (50 to 100 O improvements for men, therapy scribed to successfully treat PE. mg/day), paroxetine (20 to 40 N is time consuming and requires a Initial medical treatments for mg/day), and fluvoxamine (100 partner willing to participate. PE involved use of medications mg/day). Common reported side The start-stop method, first to inhibit alpha receptors. In a effects of SSRIs are usually tolera- introduced by Semans (1956), is small, nonrandomized study, 20 ble and include gastrointestinal an alternative treatment option mg to 30 mg of the alpha-adren- complaints and anxiety. One for treating PE. As suggested by ergic blocker phenoxybenzamine study comparing all four SSRIs the name, this technique was used successfully to treat PE with placebo reported paroxetine involves masturbatory stimula- in nine patients (Shilon, Paz, & to exert the strongest delay in ejac- tion of the penis until the sensa- Homonnai, 1984). It should be ulation (Waldinger, Hengevald, & tion of heightened arousal is met noted that a significant side effect Zwinderman, 1998). but prior to the onset of the ejac- of the medication is aspermia; A double-blind, placebo-con- ulatory reflex. The stimulation is therefore, this therapy should not trolled study compared fluoxe- then withheld until the sensation be considered in men wishing to tine (40 mg QD), sertraline (100 resolves. This is repeated until procreate. mg QD), and clomipramine (50 the man reaches the point that The tricyclic antidepressant mg QD) for the treatment of PE extravaginal stimulation occurs clomipramine was effective in (Kim & Seo, 1998). Although without ever reaching the sensa- treating PE in several double- both patient and partner sexual tion of inevitability. blind placebo-controlled trials satisfaction were statistically sig- Decreasing penile sensitivity. with doses ranging from 10 mg to nificantly higher with clomi- An alternative option for patients 50 mg per day (Girgis, El-Haggar, pramine when compared to the includes the application of 2.5 & El-Hermouzy, 1982; Haensel, SSRIs and placebo, the reported gms of prilocaine-lidocaine Rowland, & Kallan, 1996; Kim & side effects of the medication cream to the glans 30 minutes Seo, 1998; Rowland, De Gouveia were also significantly higher. Of prior to intercourse. After appli- Brazao, & Koos Slob, 2001; the remaining medications, ser- cation, a is used to hold Strassberg, De Gouveia Brazao, traline was more effective than the cream in place. In a prelimi- Rowland, Tan, & Slob, 1999). fluoxetine and placebo with fewer nary unblinded study, 81% of Possible mechanisms for action side effects than clomipramine. men reported improvements in of the medication include inhibi- Other studies evaluated if their PE (Berkovitch, Keresteci, & tion of the autonomic processes clomipramine (Haensel et al., Koren, 1995). Men can titrate the involved in the ejaculatory 1996), sertraline (Kim & Paick, degree of penile numbness by reflex, diminished psychological 1999), or paroxetine (McMahon adjusting the exposure time to arousal, or a direct anxiolytic & Touma, 1999) taken as needed

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C rather than continuously could 3.32 minutes in the 60 mg dapox- Negri, L., & Zanollo, A. (1986). be effective to increase ejaculato- etine group. Additionally, both Evoked sacral potentials in subjects O with true premature ejaculation. ry latency. All of the studies sug- 30 mg and 60 mg of dapoxetine Andrologia, 18, 583-586. N gested effectiveness in treatment were significantly better than Coolen, M.L., Allard, J., Truitt, W.A., & T using this regimen when the placebo in increasing IELT at first McKenna, K.E. (2004). Central regu- I medication is administered 12 to dose. Although the study med- lation of ejaculation. Physiology & 24 hours (clomipramine); 4 to 8 ication appeared to be well toler- Behavior, 83, 203-215. N Fanciullacci, F., Colpi, G.M., Beretta, G., hours (sertraline); or 3 to 4 hours ated, common side effects & Zanollo, A. (1988). Cortical U (paroxetine) prior to intercourse. included reports of nausea in evoked potentials in subjects with I More recently, the use of silde- 8.7% of men taking the 30 mg true premature ejaculation. nafil citrate as an adjuvant therapy dose and 20.1% of men taking Andrologia, 20, 326-330. N Gerstenberg, T.C., Levin, R.J., & Wagner, to paroxetine to treat PE was eval- the 60 mg dose. Headache was G. (1990). Erection and ejaculation G uated (Salonia et al., 2002). also reported in 5.9% and 6.8% in man. Assessment of the elec- Combination therapy with silde- respectively. Additionally, 6.8% tromyographic activity of the bulbo- cavernosus and ischiocavernosus E nafil and paroxetine improved of men reported diarrhea and time to ejaculation and sexual sat- 6.2% reported dizziness with the muscles. British Journal of Urology, 65, 395-402. D isfaction compared to paroxetine 60 mg dose. Gil-Vernet, J.M., Jr., Alvarez-Vijande, R., U alone; however, a slight increase In October 2005, this medica- Gil-Vernet, A., & Gil-Vernet, J.M. C was noted in drug-related side tion was not approved by the FDA (1994). Ejaculation in men: A effects. This was not a placebo- because the outcome of the trials dynamic endorectal ultrasonograph- A ical study. British Journal of Urology, controlled trial however, and it is did not show that dapoxetine was 73, 442-448. T unclear if phosphodiesterase sufficiently superior to placebo. Girgis, S.M., El-Haggar, S., & El- I inhibitors have a significant phar- Other drugs are being investigated. Hermouzy, S. (1982). A double-blind macologic role in treating men trial of clomipramine in premature O with PE. Conclusion ejaculation. Andrologia, 14, 364- 368. N Dapoxetine is a new fast-act- Premature ejaculation is a Godpodinoff, M.L. (1989). Premature ing selective serotonin reuptake common male sexual disorder ejaculation: Clinical subgroups and inhibitor specifically for PE. Pryor, that can have a significant impact etiology. Journal of Sex & Marital Althof, Steidle, Miloslavsky, and on the quality of life of couples. Therapy, 15, 130-134. Haensel, S.M., Klem, T.M., Hop, W.C., & Kell (2005) recently reported on Both behavioral and pharmaco- Slob, A.K. (1998). Fluoxetine and two multicenter, randomized, logical options are available and premature ejaculation: A double- double-blind, placebo-controlled effective for men presenting with blind, crossover, placebo-controlled trials. A total of 2,614 men with this problem. • study. Journal of Clinical PE were enrolled in the trials Psychopharmacology, 18, 72-77. Haensel, S.M., Rowland, D.L., & Kallan, which consisted of a 2-week References T. (1996). Clomipramine and sexual baseline period followed by a 12- American Urological Association (AUA) function in men with premature Consensus Panel. (2004). Guidelines ejaculation and controls. Journal of week treatment period. Intra- on the management of premature vaginal latency time (IELT) was Urology, 156, 1310-1315. ejaculation (pp. 1-19). Linthicum, Herberg, L.J. (1963). A hypothalamic measured by a stopwatch held by MD: AUA. mechanism causing seminal ejacula- the . After the 2- Berkovitch, M., Keresteci, A.G., & Koren, tion. Nature, 198, 219-220. week baseline period, men with G. (1995). Efficacy of prilocaine- Kara, H., Aydin, S., Yucel, M., Agargun, lidocaine cream in the treatment of M.Y., Odaba, O., & Yilmaz, Y. (1996). IELT of less than 2 minutes were premature ejaculation. Journal of randomized into three groups: The efficacy of fluoxetine in the Urology, 153, 1360-1361. treatment of premature ejaculation: placebo or dapoxetine at either Biri, H., Isen, K., Sinik, Z., Onaran, M., A double-blind placebo controlled 30 mg or 6