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Ejaculatory dysfunction
Modern Trends Edward E. WaDaeh, M.D., Associate Editor FERTILITY AND STERILITY Copyright 0 1983 The American Fertility Society
Vol. 39, No.4, April 1983 Printed in U.SA.
Ejaculatory dysfunction
Anthony J. Thomas, Jr., M.D. The Cleveland Clinic Foundation, Cleveland, Ohio
Under normal circumstances, the ejaculatory response consists of well-timed neuromuscular events that result in the expulsion of semen from the urethra. Injury to either the nerves or the muscles related to this phenomenon may result in a diminishment or absence offertility potential in the male. It should be noted that the process of ejaculation is separate from that of erection and! or orgasm. Each of these events is a distinct, realizable entity that usually occurs within close proximity of the other but is physiologically and psychodynamically independent. Although usually occurring together as a summation of sexual stimulation, orgasm is not caused by ejaculation, nor is ejaculation stimulated by orgasmic sensation. Ejaculation is basically a twofold experience: first, the expression of prostatic fluid, semen, and sperm into the posterior urethra and, second, the rhythmic expulsion of this fluid from the urethra. PHYSIOLOGY OF EJACULATION
The exact excitatory stimulus for ejaculation has not yet been clearly defined. The hypothalamus appears to play a central role; it has been shown that the dopaminergic system in the anterior hypothalamus facilitates ejaculation, while the serotonergic system inhibits this event. 1 -3 ANATOMY
The mid and tail portions of the epididymis, as well as the vas deferens, represent a persistence of the paired Wolffian ducts in the male. The vasa deferentia in the adult human measure approximately 35 cm each in length from the tail of the epididymis to termination as ejaculatory ducts Vol. 39, No.4, April 1983
traversing the prostatic urethra. The lumen of the normal vas deferens is approximately 0.4 mm in diameter, lined by columnar and cuboidal cells. The internal surface is covered with microvilli. The muscular layer is composed of both longitudinal and circular fibers, which give the vas deferens an external diameter of approximately 3 mm. Within its outer adventitial coating are abundant nerves, primarily adrenergic, as well as a rich vascular network. 4 The seminal vesicles develop at about the 13th week of embryonic life as outpouches or diverticula of the Wolffian ducts, lying posterior to the bladder and above the base of the prostate. The portion of the Wolffian ducts just proximal to the Mullerian tubercle becomes dilated simultaneously with seminal vesicular development and forms the ampulla of the vas. Distally the Wolffian ducts are found within the prostatic urethra as the paired ejaculatory ducts. NEUROPHYSIOLOGY OF EJACULATORY COMPONENTS
The ejaculatory reflex is a rather complex, although coordinated, event that can be stimulated or inhibited by either local (genital) or central (cortical) pathways. Injury or alteration of the nerves and muscles supplying the ejaculatory system may occur following various surgical procedures, trauma, or the use of certain drugs. It is well recognized that emission of semen into the urethra is under the control of the sympathet. ic nervous system. Short adrenergic fibers are numerous throughout the vas deferens, and histochemical analyses have demonstrated a high content of norepinephrine in the human vas. 5 -9 The bulbocavernosus and ischiocavernosus muscles, as well as the urogenital diaphragm, are Thomas Ejaculatory dysfunction
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offer only one means of sensory input; and as long as cortical stimulation is present and the sympathetic chain and postganglionic fibers are intact, ejaculation can still take place. 12-14 Efferent fibers responsible for seminal emission originate in the cerebral cortex (thalamus, spinothalamic centers) and course down the anterolateral columns to the thoracolumbar and sympathetic chain (TI0-L3). From these ganglia, postsynaptic adrenergic nerve fibers form a complex network overlying the area of the aortic bifurcation (superior hypogastric plexus), then disperse to either side of the rectum and bladder, mingling with the parasympathetic branches of the sacral cord. Further extension carries them to their end organs: bladder neck, vas deferens, seminal vesicles, epididymis, and prostate. Within the thin adventitial tissues there is another synapticjunction, short adrenergic fibers, branches of which terminate within the individual smooth muscle cells 15-17 (Fig. 1). THE DYNAMICS OF EJACULATION
-·-· SQnmtic --·- Sympath.tk --Sensory
Figure 1 Diagrammatic representation of the sympathetic, somatic, and sensory components of the ejaculatory systems.
responsible for seminal propulsion through the urethra and are innervated by the pudendal nerve, the somatic component of the ejaculatory system. The total ejaculatory phenomenon is controlled by cerebral factors that can inhibit or excite the process. Electrical stimulation of the preoptic area, loci in the anterior thalamus, or in close proximity to the spinothalamic fibers within the cortex will evoke seminal emission. lO In the genital region, the dorsal nerves of the penis play a part in stimulating the ejaculatory reflex. Observations made in monkeys with partial and complete transection of afferent sensory dorsal nerves noted that ejaculatory time was prolonged but not abolished when 80% to 90% of the nerve fibers were destroyed and entirely absent with complete destruction of these nerves.l1 In man, destruction of these nerves will not always abolish ejaculatory response but will prolong it. These nerves 446
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Ejaculation in man usually occurs as a synchronous, repeatable experience. The nerves and muscles act together to propel the sperm, prostatic fluid, and seminal plasma out of the urethra. Marberger 18 has listed three distinct phases that take place: (1) seminal emission, (2) formation of a pressure chamber, and (3) expulsion of fluid from the urethra. Whether the stimulus is cerebral or genital, emission occurs by contraction of the prostatic musculature, expressing its fluid into the posterior urethra, followed by the sperm-rich fraction from the ampulla and distal vas and, finally, contraction and expression of fluid from the seminal vesicles. Cineradiographic studies have shown that the straight portion of the vas deferens and seminal vesicles are not completely efficient in emptying into the proximal urethra in many instances. The ampullae, on the other hand, undergo very forceful contractions, which appears to be the "most dominant phenomena during the ejaculatory phase.,,19-21 As emission is taking place, there is a simultaneous formation of a "pressure chamber" between the vesical neck and the urogenital diaphragm. The semen is propelled distally as the urogenital diaphragm opens, and the ischiocavernosus and bulbocavernosus muscles, as well as other muscles of the pelvic floor, contract in a rhythmic Fertility and Sterility
fashion against the gradient or closed bladder neck. 22 Without complete bladder neck competence during ejaculation, most of the semen would be forced into the bladder, the path of least resistance. For many years, much work has been done concerning the role of the bladder neck in urinary control and voiding. Only recently have studies shown its physiologic importance in the mechanics of antegrade ejaculation. 23-25 The vesical neck is passively a closed structure, primarily because of its large number of elastic fibers. Studies have shown that the anterior bladder base is supplied with both cholinergic and a-adrenergic fibers. It is the stimulation of the sympathetic adrenergic nerves which creates the posterior barrier preventing semen from entering the bladder during ejaculation. Investigators have shown that there is a rhythmic contraction of the bladder neck during the emission phase. Koraitim et al. 26 have observed that most of the electrical and physical activity was from the ventral aspect of the bladder neck. Simultaneous electromyogram tr~ces of the urogenital diaphragm revealed similar rhythmic patterns preceded by periods of increased electrical activity.27-32 Stockamp and Schreiter27 demonstrated that complete closure of the vesical neck does not occur, but that there is a muscular contraction that forces the colliculus backward toward the bladder neck, plugging the lumen and creating a pocket in the posterior urethra for the semen, which is then propelled outward. The external sphincter, which opens to allow seminal emission in an anterior direction, is under the control of the somatic efferent portion of the pudendal nerves, which exit the cord via the sacral nerve plexus. Injury to this muscle or the pudendal nerve may abolish or alter the expulsion pattern.
COMMON PITFALLS IN THE DETERMINATION OF EJACULATORY FUNCTION AND/OR DYSFUNCTION
In clinical practice, the determination of ejaculatory competence is mandatory. There are, at times, some problems that may occur, leading the physician to deduce erroneously that the ejaculatory mechanism is dysfunctional. Ejaculatory normality is in part defined by the quantity of seminal fluid produced, the average Vol. 39, No.4, April 1983
being between 2 and 5 ml. A number of factors may contribute to a decreased volume of semen for an individual with normal ejaculatory ability. If the time period between the last ejaculation and collection of a specimen is too short « 24 hours), a smaller than normal volume can be expected. Since the majority of couples trying to have children are having intercourse about three times a week, an abstinence period of about 48 hours is requested prior to specimen collection. Anxiety on the part of the patient may cause an incomplete ejaculation by either not allowing for sufficient sexual excitement or preventing the full expulsion of fluid due to tension and the inability of the urogenital diaphragm to open, allowing for fluid release. This may be alleviated by the physician's allowing the patient to produce the sample in the comfort and privacy of his home, often enlisting the help of his spouse. Producing a semen sample into a too small container or one with a narrow neck opening can lead to partial collections and erroneous results. Preferably, the sample should be produced by masturbation and ejaculation directly into a wide-mouth clean or sterile jar that has been proven nontoxic to the sperm. Multiple samples are necessary before the adequacy or inadequacy of the quantity and/or quality of sperm and seminal plasma are determined. MYOPATHIC EJACULATORY DYSFUNCTION
One of the most common causes of vesical neck incompetence and retrograde ejaculation is transurethral resection of the prostate. At the age at which this procedure is performed, most men are not interested in achieving a pregnancy with their wives; and since erectile and orgasmic sensation can usually be maintained, very few are concerned with this loss. Not every man having undergone prostatectomy will have retrograde ejaculation. Rieser33 described antegrade ejaculation in more than half of the 36 patients he followed . Disruption or scarring of the elastic and muscular fibers of the vesical neck can also cause retrograde ejaculation. Twenty to 30 years ago, many young men were subjected to Y -V urethrocystoplasties of the vesical neck that were performed by well-intentioned surgeons in an apparent attempt to lower outflow resistance and prevent or correct reflux. 34 Some, but not all, of these patients may have retrograde ejaculation. It is of interest to note that Koraitim Thomas Ejaculatory dysfunction
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and AI-Ghorab
As previously noted, the neurologic stimulus effecting seminal emission and bladder neck competence is due to the thoracolumbar (sympathetic) outlet. Alterations of these nerves mechanically, chemically, or metabolically can adversely affect man's ability to ejaculate sperm effectively. Traumatic or surgical injury to the sympathetic nerves may result in either retrograde ejaculation or a complete lack of seminal emission. Retroperitoneal lymph node dissection performed on patients with nonseminomatous testicular tumors has resulted in a large percentage of young men who are free of malignant disease but who are incapable of impregnating their spouses.39, 40 In the presence of bulky disease within the retroperitoneum, it is not unusual to excise portions of the sympathetic chain in the dissection, thus disrupting the ejaculatory mechanism. More commonly, when there are negative nodes or limited macroscopic and/or microscopic disease, the postganglionic sympathetic fibers coursing about the aortic bifurcation (superior hypogastric plexus) are stripped off along with the lymphatic chains. Some of these patients will retain seminal emission but will ejaculate in a retrograde fashion. Most will lose the ability to emit semen altogether. 448
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Because testicular cancer occurs more commonly in young men who may be interested in fathering children, studies are being conducted with the aim of limiting the retroperitoneal dissection, sparing reproductive capacity while maintaining the effectiveness and high percentage of cure established in the past 10 years. 41 Until these studies are accepted as standard methods of treatment, young men with this form of ejaculatory dysfunction will present themselves for fertility evaluation and treatment. Recently, Narayan et al. 42 reviewed 55 men who had undergone extended retroperitoneal lymph node dissection and found that almost half of them recovered ejaculatory capacity. Five of ten men with retrograde ejaculation were converted to antegrade ejaculators by the use of sympathomimetic drugs. Destruction or alteration of the nerves involved with emission and antegrade ejaculation may occur as a by-product of other surgical procedures. Weinstein and Machleder43 reported that 6 of 12 patients undergoing abdominal aortic aneurysmectomy developed retrograde ejaculation. Anterior resection ofthe rectum as well as the abdominal-perineal approach have been reported to cause ejaculatory disturbances in 50% and 38%, respectively, indicating that nerve injury had occurred in the area ofthe inferior hypogastric plexus. 44 TREATMENT OF RETROGRADE EJACULATION
The diagnosis of retrograde ejaculation is easily made by examining the postejaculatory urine and finding sperm present. One would not expect a patient with a scarred or previously resected bladder neck to respond to sympathetic stimulation, because the muscular and elastic fibers are no longer intact. In order to retrieve sperm for use in insemination, surgery can be attempted, as described by Abrahams et al.,45 to restore bladder neck competency. More easily, sperm can be obtained from the bladder either by direct voiding or catheterization and irrigation. Whichever of these latter two methods is used, it is important to assure a dilute, alkaline urine in which the sperm have a greater chance of survival. This is best accomplished by encouraging an increased fluid intake and alkalinizing the urine using sodium bicarbonate the day before and the day of expected sperm retrieval. Sodium bicarbonate tablets, 600 mg, can be given every 6 hours the Fertility and Sterility
Table 1. Sympathomimetic Medications Used to Achieve Seminal Emission and/or Antegrade EjaculationB Drugs
Bromopheniramine maleate, phenylephrine hydrochloride plus phenylpropanolamine Pseudoephedrine HCI Ephedrine sulfate Phenylpropanolamine
Chlorpheniramine plus phenylpropanolamine
Dosage
Brand
Dimetapp Extentabs (A. H. Robins Co., Richmond, VA) Purebrom Compound Tabs (Purepac Pharmaceutical Co., Elizabeth, NJ) Sudafed (Burroughs Well come Co., Research Triangle Park, NC) Propadrine (Merck Sharp & Dohme, West Point, PA) Phenylpropanolamine HCI (Geneva Generics, Broomfield, CO) Ornade (Smith Kline & French Laboratories, Philadelphia, P A)
Frequency of administration Every 12 hours Every 12 hours
60mg
Every 8 hours
25 mg, 50 mg 25 mg, 50 mg
Every 8 hours Every 8 hours
75mg
Every 12 hours Every 12 hours
~o be taken by patient during the wife's periovulatory interval (approximately 10 days during midcycle) and when the semen sample is obtained.
day before and every 4 hours the day of sperm collection. Whether the patient is catheterized after ejaculation or allowed to void, urine osmolarity as well as pH is of prime importance in obtaining sperm with acceptable motility for insemination. The urine pH should be above 7.0; whereas the urine osmolarity, as determined by Mahadevan et a1. 46 and erich and Jequier,47 should be between 200 and 300 mOsmlkg water. In order to achieve this degree of dilution, it is recommended that the previously well-hydrated patient drink 500 ml of water 1 hour before ejaculation. A voided specimen is checked; and if it is above 300 mOsm/kg, another 200 ml of water is consumed. Once in the proper range, ejaculation takes place and urine is voided within 10 minutes. The urine/semen mixture is centrifuged for 10 minutes at 2000 to 3000 RPM, and the sperm pellet is resuspended in a dextrose/Ringer's solution or other appropriate milieu to a volume of 2 to 3 m1. A drop is examined for sperm concentration and motility, and the remainder is used for insemination. 33 , 48, 49 Those men with retrograde ejaculation in whom scarring of the bladder neck is not apparent may respond to the use of a-sympathomimetic medication and convert to antegrade ejaculation. 50-52 This would include not only men with bladder neck incompetence alone but also some in whom seminal emission was initially absent. Narayan et a1. 42 have pointed out that one third of the men who did not emit sperm following retroperitoneal lymph node dissection responded to sympathomimetic medication given over a 2week trial period in sequential fashion until sperm was obtained or failure of all drug trials occurred. Vol. 39, No.4, April 1983
One of the problems with some of the sympathomimetic agents used is the development of a tachyphylaxis due to a depletion of norepinephrine stores at the terminal nerve endings. Phenylpropanolamine, an a-sympathomimetic, seems to circumvent this problem and also causes less central nervous system stimulation. This drug is available in pure form or in combination with other drugs (Table 1). It should be noted that for some individuals who have undergone retroperitoneal lymph node dissection for nonseminomatous germ cell tumors, ejaculation is not an all-or-none phenomenon. Much is, of course, dependent on the extent of dissection. While most men have been noted to exhibit complete loss of seminal emission, some have intermittent or periodic episodes of retrograde ejaculation, while others have been noted to "ooze" semen and spermatozoa from the urethra minutes after the ejaculatory experience. METABOLIC CAUSES OF EJACULATORY DISORDER
Diabetes mellitus is a well-known cause of autonomic neuropathy.53-55 Rundles,56 in 1945, first reported abnormalities in sweating and temperature regulation of the skin. Since sweating is controlled by the sympathetic nervous system, it is not surprising that ejaculatory disturbances in some of these patients may also occur. This has been most commonly noted in the young adult with juvenile-onset diabetes mellitus. 57 The exact incidence of retrograde ejaculation is difficult to define, but it should be kept in mind whenever a young diabetic male presents himself for a fertility evaluation. Antegrade ejaculation may be Thomas Ejaculatory dysfunction
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Table 2. Drugs That May Adversely Affect Ejaculation Alcohol Amitriptyline Bethanidine Chlorimipramine Guanethidine sulfate Imipramine HCI Methadone Naproxen
Perphenazine Phenelzine Phenoxybenzamine HCI Phentolamine Reserpine Trifluoperazine HCI Thioridazine
achieved in some of these men by the use of sympathomimetic drugs or imipramine, an antidepressant that blocks the nerve endings from restoring norepinephrine. 58
DRUGS CAUSING EJACULATORY DISTURBANCE
In our attempt to treat disorders such as hypertension or affect an improvement in the psychoneurotic or depressed patient, a variety of drugs are often used. Although each of these drugs can be beneficial as to its primary activity, secondary chemical or neurologic sequela may occur which impairs ejaculatory ability. 59-62 Table 2 lists commonly used drugs which may cause ejaculatory disturbance. Some of these may have antiadrenergic properties preventing complete closure of the bladder neck, others may inhibit emission of semen into the urethra, and still others, the psychotropics in particular, may cause retarded ejaculatory response with prolonged latency period between intromission and ejaculation. SPINAL CORD INJURY
Spinal cord-injured patients suffer a variety of sexual incapabilities dependent on the level of their spinal injury. Bors and Comarr,63 Comarr,64 and Comarr and Gunderson65 have succinctly detailed the sexual capability in a large series of patients. Those men with complete upper motor neuron lesions rarely ejaculated, although about 70% are capable of erection sufficient for intercourse. With incomplete upper motor neuron lesions, men exhibited a somewhat greater frequency of ejaculation. Very few men with complete lower motor neuron lesions were likely to achieve erection or ejaculate. With incomplete lower motor neuron lesions, the majority of men maintained an erection sufficient for intercourse, and about half of these retained their ability to ejaculate. If one considers all the men in these series, 450
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only 3% were able to achieve a pregnancy with their spouse. Due to the fact that there has been greater emphasis on the care and rehabilitation of the spinal cord-injured patient and consequent longer life expectancy, more of these men and women are interested in and capable of full and active lives, including marriage and offspring. 66 Since ejaculation does not occur in the majority of these patients, various methods have been proposed to stimulate these nerve-injured centers to cause emission and expulsion of sperm. 67 -71 Reports in veterinary medicine journals on the use of electrical stimulus to achieve ejaculation in animals began appearing in the 1930s. Ten to 15 years later, such stimulation was attempted in paraplegic men; but because of "electrical uncertainties" and fear of injury to the patient, this technique has never achieved any great degree of acceptance. Even with today's higher technology, although local injury can be avoided, the success in obtaining fertile sperm in this manner has been limited. Francois et al. 69 performed 116 electrostimulations, resulting in 63 ejaculations. Forty-two percent of patients ejaculated, and only one pregnancy occurred. Brindley 71 applied his modified technique to 84 patients, 50 responding either with antegrade or retrograde ejaculation. Again, only one pregnancy was achieved. One of the significant factors, with this and other techniques, is the potential occurrence of autonomic dysreflexia. Frankel and Mathias70 described the mandatory laboratory equipment as being a "cardiac arrest trolley" with various medications such as pentolinium, phentolamine, propranolol, and prostaglandin estradiol. Although outwardly appearing to be somewhat effective in obtaining sperm, the quality is usually not adequate, and the risks, particularly for those men with high spinal lesions, appear to outweigh the potential benefits. Due to the varied and incomplete lesions noted with spinal cord injuries, the occurrence of ejaculation is obviously uncommon. Sperm, if available at all, varies in quality and this quality appears to lessen with time from injury. Whether this is due to neurovascular changes or temperature-related phenomena is unclear at present. 72 -74 The use of the electrovibrator has met with some success in patients with various levels of spinal cord injuries. 68-75 Amelar et al. 76 have described a modification to the hand-held vibrator, allowing the semen to be ejaculated and collected Fertility and Sterility
individual patient with the use of a computer and a constant arterial pressure monitor. It is quite obvious that this method is not to be considered a "routine procedure" and should only be carried out where strict monitoring and immediate and appropriate therapy can be rendered. CONGENITAL CAUSES OF EJACULATORY ABNORMALITIES
Figure 2 Obstruction of the ejaculatory ducts. Note dilated, tortuous vas deferens emptying into the cystic structure (Mullerian duct cyst).
to be used for insemination. This technique has been found to be useful and safe but effective in only a few patients. Undoubtedly, the most interesting technique for achieving erection and ejaculation is that described by Guttman and Walsh 77 using intrathecal injection of neostigmine. Originally proposed in 1947, this drug has been shown to elicit erection and ejaculation in a large percentage of males. Single or multiple ejaculations were observed in approximately 60% of 70 men with complete upper motor neuron lesions and 75% of 29 men with incomplete upper motor neuron lesions. Two thirds of those men with complete lower motor neuron lesions failed to ejaculate. Two pregnancies were achieved by artificial insemination with homologous semen but ended in spontaneous abortions. Again, one of the major drawbacks with this technique is the incidence of autonomic dysreflexia, particularly in those men with high cervical lesions. Drugs must be immediately available for treatment. Lipshultz et al. 58 have recommended the use of Nitroprusside (Roche Laboratories, Division of Hoffmann-La Roche Inc., Nutley, NJ) to control this response. The drug is titrated to the Vol. 39, No.4, April 1983
Although uncommon, congenital absence of the vas deferens and seminal vesicles does occur, on either one or both sides. When unilateral, it is often associated with ipsilateral absence of the kidney, but the ejaculatory volume is usually normal. With bilateral absence of the vas, the ejaculated fluid volume is small, less than 1 ml, and acidic and, of course, contains no sperm. Children who are born with bladder exstrophy may have normal spermatogenesis; but in the attempt to reconstruct the bladder and urethra, the ejaculatory ducts may be obstructed or retrograde ejaculation may occur due to the absence of a competent bladder neck. 78 Young men with a corrected epispadias may have ejaculatory disturbances due to irregularity and/or stricture of the urethra as well as poor development of the muscles involved with semen propulsion through the urethra. Rarely, azoospermia and a small ejaculatory volume may be found due to a congenital obstruction of the ejaculatory ducts, which may empty into a Mullerian duct cyst (Fig. 2). In such a case, transurethral resection or unroofing may provide adequate drainage and consequent fertility.79, 80 FUNCTIONAL EJACULATORY DISORDERS
Premature ejaculation rarely affects fertility potential unless ejaculation occurs prior to vaginal penetration. The treatment of this common malady has been highly successful in the wellmotivated individual. 81 -83 Retarded ejaculation represents a significant problem for the couple trying to achieve a pregnancy. Most commonly, ejaculation is simply not possible during coital activity.84-86 Although initially thought to be a rare phenomenon, recent studies have shown an increase in the number of patients complaining of ejaculatory incompetence. Kaplan84 described an incomplete form of this problem where orgasmic sensation was intact but the semen would ooze from the urethra rather Thomas Ejaculatory dysfunction
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than be expelled vigorously by the contraction of the perineal musculature. There are a number of psychodynamic formulations to explain both premature and retarded ejaculation. Suffice it to say that if no organic cause can be found, appropriate counseling is indicated. If, in the case of retarded ejaculation, semen is able to be obtained by masturbation or electrovibration, artificial insemination by homologous semen can be carried out if the sperm quality is adequate. REFERENCES 1. Herberg LJ: The hypothalamic mechanism causing seminal ejaculation. Nature 198:219, 1963 2. Kimura Y, Kisaki N, Sakurada S, Tadano T: On the brain monoaminergic systems relating to ejaculation. I. Brain dopamine and ejaculation. Andrologia 8:313, 1976 3. Kimura Y, Kisaki N, Sakurada S, Tadano T: On the brain monoaminergic systems relating to ejaculation. II. Brain serotonin and ejaculation. Andrologia 9:50, 1977 4. Brueschke EE, Zaneveld LJD, Rodzen R, Berns D: Development of a reversible vas deferens occlusive device. m. Morphology of the human and dog vas deferens: a study with the scanning electron microscope. Fertil Steril 25:687, 1974 5. Anton PG, McGrath JC: Further evidence for adrenergic transmiBBion in the human vas deferens. J Physiol (Lond) 273:45, 1977 6. McLeod 00, Reynolds DG, Demaree GE: Some pharmacologic characteristics of the human vas deferens. Invest Urol 10:338, 1973 7. Baumgarten HG, Holstein AF, Rosengren E: Arrangement, ultrastructure, and adrenergic innervation of smooth musculature of the ductuli efferentes, ductus epididymis and ductus deferens of man. Zelforsch 120:37, 1971 8. Learmouth JR: A contribution to the neurophysiology of the urinary bladder in man. Brain 54:147, 1931 9. Davidson JM: Neurohormonal bases of male sexual behavior. In International Review of Physiology, Edited by RG Greep. Baltimore, University Park Press, 1977, p 225 10. MacLean PP, Dua S, Denniston RH: Cerebral localization for scratching and seminal discharge. Arch Neurol 9:485, 1963 11. Herbert J: The role of the dorsal nerves of the penis in the sexual behavior of the male rhesus monkey. Physiol Behav 10:293, 1973 12. Bors E, Comarr AE: Neurologic disturbances of sexual function. Urol Surv 10:191, 1960 13. Coman AE: Sexual concepts in traumatic cord and cauda equina lesions. J Urol106:375, 1971 14. Comarr AE: Sexual function among patients with spinal cord injury. Urol Int 25:134, 1970 15. Dail WG, Evan AP: Experimental evidence indicating that the penis of the rat is innervated by short adrenergic neurons. Am J Anat 141:203, 1972 16. Owman CH, Sjoberg NO: The importance of short adrenergic neurons in the seminal emission mechanism of rat, guinea pig, and man. J Reprod Fertil 28:379, 1972 452
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17. Sjostrand NO: The adrenergic innervation of the vas deferens and the accessory male genital gland. Acta Physiol Scand 65:257, 1965 18. Marberger H: The mechanisms of ejaculation. Basic Life Sci (Part B) 4:99, 1974 19. Ichijo S, Sigg C, Nagasawa M, Siraiwa Y: Vasoseminal vesiculography before and after ejaculation. Urol Int 36:35,1981 20. Mitsuya H, Asai J, Suyama K, Ushida T, Hosoe K: Application of x-ray cinematography in urology. I. Mechanism of ejaculation. J Urol 83:86, 1960 21. Guha SK, Kaur H, Ahmed AM: Mechanics of spermatic fluid transport in the vas deferens. Med BioI Eng Comput (continues Med BioI Eng) 13:518, 1975 22. Gallizia P: The smooth sphincter of the vesical neck, a genital organ. Urol Int 27:341, 1972 23. Kimura Y, Miyata K, Adachi K, Kisaki N: Peripheral nerves controlling the closure of internal urethral orifice during ejaculation. Urol Int 30:218, 1975 24. Kimura Y, Adachi K, Kisaki N, !se K: Role of alphaadrenergic receptor mechanism in closure of the internal urethral orifice during the ejaculation. Urol Int 30:341, 1975 25. Tanagho E, Smith DR: The anatomy and function of the bladder neck. Br J Urol 38:54, 1966 26. Koraitim M, Schafer W, Melachior H, Lutzeyer W: Dynamic activity of the bladder neck and external sphincter in ejaculation. Urology 10:130, 1977 27. Stockamp K, Schreiter F: Function of the posterior urethra in ejaculation and its importance for urine control. Urol Int 29:226,1974 28. Benson GS, Sarshik S, Raezer D, Wein A: Bladder muscle contractility: comparative effects and mechanisms of action of atropine, propantheline flavoxate, and imipramine. Urology 9:31, 1977 29. Gosling JA, Dixon JS, Lendon RG: The autonomic innervation of the human male and female bladder neck and proximal urethra. J Urol 118:302, 1977 30. Naomidis S: The physiology and pathology of the urinary bladder neck. Urol Int 27:393, 1972 31. Purohit R, Beckett S: Penile pressures and muscle activity aSBociated with erection and ejaculation of dog. Am J Physiol 231:1343, 1976 32. Peterson I, Stener I: The electromyographical study of the striated urethral sphincter, the striated anal sphincter, and the levator ani muscle during ejaculation. Electromyogr Clin Neurophysiol (continues Electromyography) 10:23,1970 33. Rieser C: The etiology of retrograde ejaculation and a method for insemination. Fertil Steril 12:488, 1961 34. Ochsner MG, Bums E, Henry HH: Incidence of retrograde ejaculation following bladder neck revision as a child. J Urol 104:596, 1970 35. Koraitim M, AI-Ghorab M: Normal ejaculation after YV urethrocystoplasty. Br J UroI42:462, 1970 36. Gute D, Chute R, Baron J: Bladder neck revision for obstruction in men: a clinical study reporting normal ejaculation postoperatively. J Urol 99:744, 1968 37. Sandler B: Idiopathic retrograde ejaculation. Fertil Steril 32:474, 1979 38. Keiserman WM, Dubin L, Amelar RD: A new type of retrograde ejaculation: report of three cases. Fertil Steril 25:1071, 1974
Fertility and Sterility
39. Kedia KR, Markland C, Fraley EE: Sexual function following high retroperitoneal lymphadenectomy. J Urol 114:237,1975 40. Bracken RB, Johnson DE: Sexual function and fecundity after treatment for testicular tumors. Urology 7:35, 1976 41. Hermanek P, Siegel A: Necessary extent of lymph node dissection in testicular tumours: a histopathological investigation. Eur UroI8:135, 1982 42. Narayan P, Lange PH, Fraley EE: Ejaculation and fertility after extended retroperitoneal lymph node dissection for testicular cancer. J Urol 127:685, 1982 43. Weinstein MH, Machleder HI: Sexual function after aorto-iliac surgery. Ann Surg 181:787, 1975 44. Williams DI, Watson PC, Golligher JC, Riches EW, Gabriel WB, Pyrah LN: Discussion on urological complications of excision of the rectum. Proc R Soc Med 44:819, 1951 45. Abrahams JI, Solish GI, Boorhan P, Waterhouse RK: The surgical correction of retrograde ejaculation. J Urol 114:888, 1975 46. Mahadevan M, Leeton JF, Trounson AO: Noninvasive method of semen collection for successful artificial insemination in a. case of retrograde ejaculation. Fertil Steril 36:243, 1981 47. Crich JP, Jequier AM: Infertility in men with retrograde ejaculation: the action of urine on sperm motility, and a simple method for achieving antegrade ejaculation. Fertil Steril 30:572, 1978 48. Hotchkiss RS, Pinto AB, Kleegman S: Artificial insemination with semen recovered from the bladder. Fertil Steril 6:37, 1955 49. Fischer IC, Coats EC: Sterility due to retrograde ejaculation of semen: report of pregnancy achieved by autoinsemination. Obstet Gynecol 4:352, 1954 50. Thiagarajah S, Vaughan ED Jr, Kitchin JD ill: Retrograde ejaculation: successful pregnancy following combined sympathomimetic medication and insemination. Fertil Steril 30:96, 1978 51. Stewart BH, Bergant JA: Correction of retrograde ejaculation to sympathomimetic medication: preliminary report. Fertil SteriI25:1073, 1974 52. Kragt F, Schellen A: Clinical report of some cases with retrograde ejaculation. Andrologia 10:381, 1979 53. Hosking DJ, Bennett T, Hampton JR: Diabetic autonomic neuropathy. Diabetes 27:1043, 1978 54. Kolodny RC, Kahn CB, Goldstein HH, Barnett DM: Sexual dysfunction in diabetic men. Diabetes 23:306,1974 55. Odel lIM, Roth GM, Keating FR: Autonomic neuropathy simulating the effects of sympathectomy as a complication of diabetes mellitus. Diabetes 4:92, 1955 56. Rundles RW: Diabetic neuropathy: general review with report of 125 cases. Medicine (Baltimore) 24:111, 1945 57. Greene LF, Kelalis PP: Retrograde ejaculation in semen due to diabetic neuropathy. J UroI98:693, 1968 58. Lipshultz LI, McConnell J, Benson GS: Current concepts of the mechanisms of ejaculation: normal and abnormal states. J Reprod Med 26:499, 1981 59. Segraves RT: Male sexual dysfunction and psychoactive drug use: review of a common relationship. Postgrad Med 71:227, 1982 60. BUlpitt DJ, Dollery CT: Side effects of hypotensive agents evaluated by a self administered questionnaire. Br Med J 3:485,1973
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61. Ahlenius S, Heimann M, Larsson K: Prolongation of the ejaculation latency in the male rat by Thioridazine and Chlorimipramine. Psychopharmacology (Berlin) 65: 137, 1979 62. Innes IR, Nickerson M: Norepinephrine, epinephrine and the sympathomimetic amines. In The Pharmacological Basis of Therapeutics, Edited by LS Goodman, A Gilman. New York, MacMillan Publishing, 1975, p 477 63. Bors E, Comarr AE: Neurological disturbances of sexual function. Urol Surv 10:191, 1960 64. Comarr AE: Sexual function among patients with spinal cord injury. Urol Int 25:134, 1970 65. Comarr AE, Gunderson BB: Sexual function in traumatic paraplegia and quadraplegia. Am J Nurs 275:250, 1975 66. Masham B: The psychological and practical aspects of sex in the marriage for the paraplegic. Proc R Soc Med 66:133, 1973. 67. Rossier AB, Ziegler WH, Duchosal PW, Meylan J: Sexual function and dysreflexia. Paraplegia 9:51, 1971 68. Brindley GS: Reflex ejaculation under vibratory stimulation in paraplegic men. Paraplegia 19:299, 1981 69. Francois N, Maury M, Jouannet D, David G, Vacant J: Electro-ejaculation of a complete paraplegic followed by pregnancy. Paraplegia 16:248, 1978 70. Frankel HL, Mathias CJ: Severe hypertension in patients with high spinal cord lesions undergoing electro-ejaculation: management with prostaglandin E 2 • Paraplegia 18:293, 1980 71. Brindley GS: Electro-ejaculation: its technique, neurological implications and uses. J Neurol Neurosurg Psychiatry 44:9,. 1981 72. Brindley GS: Deep scrotal temperature and the effect on it of clothing, air temperature, activity, posture and paraplegia. Br J Urol 54:49, 1982 73. David A, Ohry A, Rozin R: Spinal cord injuries: male infertility aspects. Paraplegia 15:11, 1977 74. Higgins GE: Sexual response in spinal cord injured adults: a review of the literature. Arch Sex Behav 8:173, 1979 75. Tarabulcy E: Sexual function in the normal and in paraplegia. Paraplegia 10:201, 1972 76. Amelar RD, Dubin L, Walsh PC: Male Infertility. Philadelphia, W. B. Saunders, 1977; p 208 77. Guttman L, Walsh JJ: Prostigmin assessment test offertility in spinal man. Paraplegia 9:39, 1971 78. Hanna NK, Williams DI: Genital function in males with vesical exstrophy and epispadias. Br J Urol 44:169, 1972 79. Brooks RT: Cyst of the ejaculatory duct: case report. J Urol 101:881, 1969 SO. Furtado AJL: Three cases of cystic seminal vesicle associated with unilateral renal agenesis. Br J Urol 45:536, 1973 81. Masters WH, Johnson VE: Human Sexual Inadequacy. Boston, Little, Brown & Co., 1970, p 92 82. Semmens JP, Semmens FJ: Premature ejaculation and impotence: male problems with gynecologic implications. Clin Obstet Gynecol 21:223, 1978 83. Semans JH: Premature ejaculation: a new approach . South Med J 49:353, 1956 84. Kaplan HS: The New Sex Therapy. New York, a Brunner/Mazel Publication, Quadrangle/New York Times Book Co., 1974, p 319
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85. Munjak. DJ, Kanno PH: Retarded ejaculation: a review. Arch Sex Behav 8:139, 1979
86. Nininger JE: Inhibition of ejaculation at orgasm. NY State J Med 79:725, 1979
Received December 6, 1982. Reprint requests: Anthony J. Thomas, Jr., M.D., Head, Section of Male Infertility, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.
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Fertility and Sterility
Vol. 39, No.4, April 1983 Printed in U.SA.
Ejaculatory dysfunction
Anthony J. Thomas, Jr., M.D. The Cleveland Clinic Foundation, Cleveland, Ohio
Under normal circumstances, the ejaculatory response consists of well-timed neuromuscular events that result in the expulsion of semen from the urethra. Injury to either the nerves or the muscles related to this phenomenon may result in a diminishment or absence offertility potential in the male. It should be noted that the process of ejaculation is separate from that of erection and! or orgasm. Each of these events is a distinct, realizable entity that usually occurs within close proximity of the other but is physiologically and psychodynamically independent. Although usually occurring together as a summation of sexual stimulation, orgasm is not caused by ejaculation, nor is ejaculation stimulated by orgasmic sensation. Ejaculation is basically a twofold experience: first, the expression of prostatic fluid, semen, and sperm into the posterior urethra and, second, the rhythmic expulsion of this fluid from the urethra. PHYSIOLOGY OF EJACULATION
The exact excitatory stimulus for ejaculation has not yet been clearly defined. The hypothalamus appears to play a central role; it has been shown that the dopaminergic system in the anterior hypothalamus facilitates ejaculation, while the serotonergic system inhibits this event. 1 -3 ANATOMY
The mid and tail portions of the epididymis, as well as the vas deferens, represent a persistence of the paired Wolffian ducts in the male. The vasa deferentia in the adult human measure approximately 35 cm each in length from the tail of the epididymis to termination as ejaculatory ducts Vol. 39, No.4, April 1983
traversing the prostatic urethra. The lumen of the normal vas deferens is approximately 0.4 mm in diameter, lined by columnar and cuboidal cells. The internal surface is covered with microvilli. The muscular layer is composed of both longitudinal and circular fibers, which give the vas deferens an external diameter of approximately 3 mm. Within its outer adventitial coating are abundant nerves, primarily adrenergic, as well as a rich vascular network. 4 The seminal vesicles develop at about the 13th week of embryonic life as outpouches or diverticula of the Wolffian ducts, lying posterior to the bladder and above the base of the prostate. The portion of the Wolffian ducts just proximal to the Mullerian tubercle becomes dilated simultaneously with seminal vesicular development and forms the ampulla of the vas. Distally the Wolffian ducts are found within the prostatic urethra as the paired ejaculatory ducts. NEUROPHYSIOLOGY OF EJACULATORY COMPONENTS
The ejaculatory reflex is a rather complex, although coordinated, event that can be stimulated or inhibited by either local (genital) or central (cortical) pathways. Injury or alteration of the nerves and muscles supplying the ejaculatory system may occur following various surgical procedures, trauma, or the use of certain drugs. It is well recognized that emission of semen into the urethra is under the control of the sympathet. ic nervous system. Short adrenergic fibers are numerous throughout the vas deferens, and histochemical analyses have demonstrated a high content of norepinephrine in the human vas. 5 -9 The bulbocavernosus and ischiocavernosus muscles, as well as the urogenital diaphragm, are Thomas Ejaculatory dysfunction
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offer only one means of sensory input; and as long as cortical stimulation is present and the sympathetic chain and postganglionic fibers are intact, ejaculation can still take place. 12-14 Efferent fibers responsible for seminal emission originate in the cerebral cortex (thalamus, spinothalamic centers) and course down the anterolateral columns to the thoracolumbar and sympathetic chain (TI0-L3). From these ganglia, postsynaptic adrenergic nerve fibers form a complex network overlying the area of the aortic bifurcation (superior hypogastric plexus), then disperse to either side of the rectum and bladder, mingling with the parasympathetic branches of the sacral cord. Further extension carries them to their end organs: bladder neck, vas deferens, seminal vesicles, epididymis, and prostate. Within the thin adventitial tissues there is another synapticjunction, short adrenergic fibers, branches of which terminate within the individual smooth muscle cells 15-17 (Fig. 1). THE DYNAMICS OF EJACULATION
-·-· SQnmtic --·- Sympath.tk --Sensory
Figure 1 Diagrammatic representation of the sympathetic, somatic, and sensory components of the ejaculatory systems.
responsible for seminal propulsion through the urethra and are innervated by the pudendal nerve, the somatic component of the ejaculatory system. The total ejaculatory phenomenon is controlled by cerebral factors that can inhibit or excite the process. Electrical stimulation of the preoptic area, loci in the anterior thalamus, or in close proximity to the spinothalamic fibers within the cortex will evoke seminal emission. lO In the genital region, the dorsal nerves of the penis play a part in stimulating the ejaculatory reflex. Observations made in monkeys with partial and complete transection of afferent sensory dorsal nerves noted that ejaculatory time was prolonged but not abolished when 80% to 90% of the nerve fibers were destroyed and entirely absent with complete destruction of these nerves.l1 In man, destruction of these nerves will not always abolish ejaculatory response but will prolong it. These nerves 446
Thomas Ejaculatory dysfunction
Ejaculation in man usually occurs as a synchronous, repeatable experience. The nerves and muscles act together to propel the sperm, prostatic fluid, and seminal plasma out of the urethra. Marberger 18 has listed three distinct phases that take place: (1) seminal emission, (2) formation of a pressure chamber, and (3) expulsion of fluid from the urethra. Whether the stimulus is cerebral or genital, emission occurs by contraction of the prostatic musculature, expressing its fluid into the posterior urethra, followed by the sperm-rich fraction from the ampulla and distal vas and, finally, contraction and expression of fluid from the seminal vesicles. Cineradiographic studies have shown that the straight portion of the vas deferens and seminal vesicles are not completely efficient in emptying into the proximal urethra in many instances. The ampullae, on the other hand, undergo very forceful contractions, which appears to be the "most dominant phenomena during the ejaculatory phase.,,19-21 As emission is taking place, there is a simultaneous formation of a "pressure chamber" between the vesical neck and the urogenital diaphragm. The semen is propelled distally as the urogenital diaphragm opens, and the ischiocavernosus and bulbocavernosus muscles, as well as other muscles of the pelvic floor, contract in a rhythmic Fertility and Sterility
fashion against the gradient or closed bladder neck. 22 Without complete bladder neck competence during ejaculation, most of the semen would be forced into the bladder, the path of least resistance. For many years, much work has been done concerning the role of the bladder neck in urinary control and voiding. Only recently have studies shown its physiologic importance in the mechanics of antegrade ejaculation. 23-25 The vesical neck is passively a closed structure, primarily because of its large number of elastic fibers. Studies have shown that the anterior bladder base is supplied with both cholinergic and a-adrenergic fibers. It is the stimulation of the sympathetic adrenergic nerves which creates the posterior barrier preventing semen from entering the bladder during ejaculation. Investigators have shown that there is a rhythmic contraction of the bladder neck during the emission phase. Koraitim et al. 26 have observed that most of the electrical and physical activity was from the ventral aspect of the bladder neck. Simultaneous electromyogram tr~ces of the urogenital diaphragm revealed similar rhythmic patterns preceded by periods of increased electrical activity.27-32 Stockamp and Schreiter27 demonstrated that complete closure of the vesical neck does not occur, but that there is a muscular contraction that forces the colliculus backward toward the bladder neck, plugging the lumen and creating a pocket in the posterior urethra for the semen, which is then propelled outward. The external sphincter, which opens to allow seminal emission in an anterior direction, is under the control of the somatic efferent portion of the pudendal nerves, which exit the cord via the sacral nerve plexus. Injury to this muscle or the pudendal nerve may abolish or alter the expulsion pattern.
COMMON PITFALLS IN THE DETERMINATION OF EJACULATORY FUNCTION AND/OR DYSFUNCTION
In clinical practice, the determination of ejaculatory competence is mandatory. There are, at times, some problems that may occur, leading the physician to deduce erroneously that the ejaculatory mechanism is dysfunctional. Ejaculatory normality is in part defined by the quantity of seminal fluid produced, the average Vol. 39, No.4, April 1983
being between 2 and 5 ml. A number of factors may contribute to a decreased volume of semen for an individual with normal ejaculatory ability. If the time period between the last ejaculation and collection of a specimen is too short « 24 hours), a smaller than normal volume can be expected. Since the majority of couples trying to have children are having intercourse about three times a week, an abstinence period of about 48 hours is requested prior to specimen collection. Anxiety on the part of the patient may cause an incomplete ejaculation by either not allowing for sufficient sexual excitement or preventing the full expulsion of fluid due to tension and the inability of the urogenital diaphragm to open, allowing for fluid release. This may be alleviated by the physician's allowing the patient to produce the sample in the comfort and privacy of his home, often enlisting the help of his spouse. Producing a semen sample into a too small container or one with a narrow neck opening can lead to partial collections and erroneous results. Preferably, the sample should be produced by masturbation and ejaculation directly into a wide-mouth clean or sterile jar that has been proven nontoxic to the sperm. Multiple samples are necessary before the adequacy or inadequacy of the quantity and/or quality of sperm and seminal plasma are determined. MYOPATHIC EJACULATORY DYSFUNCTION
One of the most common causes of vesical neck incompetence and retrograde ejaculation is transurethral resection of the prostate. At the age at which this procedure is performed, most men are not interested in achieving a pregnancy with their wives; and since erectile and orgasmic sensation can usually be maintained, very few are concerned with this loss. Not every man having undergone prostatectomy will have retrograde ejaculation. Rieser33 described antegrade ejaculation in more than half of the 36 patients he followed . Disruption or scarring of the elastic and muscular fibers of the vesical neck can also cause retrograde ejaculation. Twenty to 30 years ago, many young men were subjected to Y -V urethrocystoplasties of the vesical neck that were performed by well-intentioned surgeons in an apparent attempt to lower outflow resistance and prevent or correct reflux. 34 Some, but not all, of these patients may have retrograde ejaculation. It is of interest to note that Koraitim Thomas Ejaculatory dysfunction
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and AI-Ghorab
As previously noted, the neurologic stimulus effecting seminal emission and bladder neck competence is due to the thoracolumbar (sympathetic) outlet. Alterations of these nerves mechanically, chemically, or metabolically can adversely affect man's ability to ejaculate sperm effectively. Traumatic or surgical injury to the sympathetic nerves may result in either retrograde ejaculation or a complete lack of seminal emission. Retroperitoneal lymph node dissection performed on patients with nonseminomatous testicular tumors has resulted in a large percentage of young men who are free of malignant disease but who are incapable of impregnating their spouses.39, 40 In the presence of bulky disease within the retroperitoneum, it is not unusual to excise portions of the sympathetic chain in the dissection, thus disrupting the ejaculatory mechanism. More commonly, when there are negative nodes or limited macroscopic and/or microscopic disease, the postganglionic sympathetic fibers coursing about the aortic bifurcation (superior hypogastric plexus) are stripped off along with the lymphatic chains. Some of these patients will retain seminal emission but will ejaculate in a retrograde fashion. Most will lose the ability to emit semen altogether. 448
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Because testicular cancer occurs more commonly in young men who may be interested in fathering children, studies are being conducted with the aim of limiting the retroperitoneal dissection, sparing reproductive capacity while maintaining the effectiveness and high percentage of cure established in the past 10 years. 41 Until these studies are accepted as standard methods of treatment, young men with this form of ejaculatory dysfunction will present themselves for fertility evaluation and treatment. Recently, Narayan et al. 42 reviewed 55 men who had undergone extended retroperitoneal lymph node dissection and found that almost half of them recovered ejaculatory capacity. Five of ten men with retrograde ejaculation were converted to antegrade ejaculators by the use of sympathomimetic drugs. Destruction or alteration of the nerves involved with emission and antegrade ejaculation may occur as a by-product of other surgical procedures. Weinstein and Machleder43 reported that 6 of 12 patients undergoing abdominal aortic aneurysmectomy developed retrograde ejaculation. Anterior resection ofthe rectum as well as the abdominal-perineal approach have been reported to cause ejaculatory disturbances in 50% and 38%, respectively, indicating that nerve injury had occurred in the area ofthe inferior hypogastric plexus. 44 TREATMENT OF RETROGRADE EJACULATION
The diagnosis of retrograde ejaculation is easily made by examining the postejaculatory urine and finding sperm present. One would not expect a patient with a scarred or previously resected bladder neck to respond to sympathetic stimulation, because the muscular and elastic fibers are no longer intact. In order to retrieve sperm for use in insemination, surgery can be attempted, as described by Abrahams et al.,45 to restore bladder neck competency. More easily, sperm can be obtained from the bladder either by direct voiding or catheterization and irrigation. Whichever of these latter two methods is used, it is important to assure a dilute, alkaline urine in which the sperm have a greater chance of survival. This is best accomplished by encouraging an increased fluid intake and alkalinizing the urine using sodium bicarbonate the day before and the day of expected sperm retrieval. Sodium bicarbonate tablets, 600 mg, can be given every 6 hours the Fertility and Sterility
Table 1. Sympathomimetic Medications Used to Achieve Seminal Emission and/or Antegrade EjaculationB Drugs
Bromopheniramine maleate, phenylephrine hydrochloride plus phenylpropanolamine Pseudoephedrine HCI Ephedrine sulfate Phenylpropanolamine
Chlorpheniramine plus phenylpropanolamine
Dosage
Brand
Dimetapp Extentabs (A. H. Robins Co., Richmond, VA) Purebrom Compound Tabs (Purepac Pharmaceutical Co., Elizabeth, NJ) Sudafed (Burroughs Well come Co., Research Triangle Park, NC) Propadrine (Merck Sharp & Dohme, West Point, PA) Phenylpropanolamine HCI (Geneva Generics, Broomfield, CO) Ornade (Smith Kline & French Laboratories, Philadelphia, P A)
Frequency of administration Every 12 hours Every 12 hours
60mg
Every 8 hours
25 mg, 50 mg 25 mg, 50 mg
Every 8 hours Every 8 hours
75mg
Every 12 hours Every 12 hours
~o be taken by patient during the wife's periovulatory interval (approximately 10 days during midcycle) and when the semen sample is obtained.
day before and every 4 hours the day of sperm collection. Whether the patient is catheterized after ejaculation or allowed to void, urine osmolarity as well as pH is of prime importance in obtaining sperm with acceptable motility for insemination. The urine pH should be above 7.0; whereas the urine osmolarity, as determined by Mahadevan et a1. 46 and erich and Jequier,47 should be between 200 and 300 mOsmlkg water. In order to achieve this degree of dilution, it is recommended that the previously well-hydrated patient drink 500 ml of water 1 hour before ejaculation. A voided specimen is checked; and if it is above 300 mOsm/kg, another 200 ml of water is consumed. Once in the proper range, ejaculation takes place and urine is voided within 10 minutes. The urine/semen mixture is centrifuged for 10 minutes at 2000 to 3000 RPM, and the sperm pellet is resuspended in a dextrose/Ringer's solution or other appropriate milieu to a volume of 2 to 3 m1. A drop is examined for sperm concentration and motility, and the remainder is used for insemination. 33 , 48, 49 Those men with retrograde ejaculation in whom scarring of the bladder neck is not apparent may respond to the use of a-sympathomimetic medication and convert to antegrade ejaculation. 50-52 This would include not only men with bladder neck incompetence alone but also some in whom seminal emission was initially absent. Narayan et a1. 42 have pointed out that one third of the men who did not emit sperm following retroperitoneal lymph node dissection responded to sympathomimetic medication given over a 2week trial period in sequential fashion until sperm was obtained or failure of all drug trials occurred. Vol. 39, No.4, April 1983
One of the problems with some of the sympathomimetic agents used is the development of a tachyphylaxis due to a depletion of norepinephrine stores at the terminal nerve endings. Phenylpropanolamine, an a-sympathomimetic, seems to circumvent this problem and also causes less central nervous system stimulation. This drug is available in pure form or in combination with other drugs (Table 1). It should be noted that for some individuals who have undergone retroperitoneal lymph node dissection for nonseminomatous germ cell tumors, ejaculation is not an all-or-none phenomenon. Much is, of course, dependent on the extent of dissection. While most men have been noted to exhibit complete loss of seminal emission, some have intermittent or periodic episodes of retrograde ejaculation, while others have been noted to "ooze" semen and spermatozoa from the urethra minutes after the ejaculatory experience. METABOLIC CAUSES OF EJACULATORY DISORDER
Diabetes mellitus is a well-known cause of autonomic neuropathy.53-55 Rundles,56 in 1945, first reported abnormalities in sweating and temperature regulation of the skin. Since sweating is controlled by the sympathetic nervous system, it is not surprising that ejaculatory disturbances in some of these patients may also occur. This has been most commonly noted in the young adult with juvenile-onset diabetes mellitus. 57 The exact incidence of retrograde ejaculation is difficult to define, but it should be kept in mind whenever a young diabetic male presents himself for a fertility evaluation. Antegrade ejaculation may be Thomas Ejaculatory dysfunction
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Table 2. Drugs That May Adversely Affect Ejaculation Alcohol Amitriptyline Bethanidine Chlorimipramine Guanethidine sulfate Imipramine HCI Methadone Naproxen
Perphenazine Phenelzine Phenoxybenzamine HCI Phentolamine Reserpine Trifluoperazine HCI Thioridazine
achieved in some of these men by the use of sympathomimetic drugs or imipramine, an antidepressant that blocks the nerve endings from restoring norepinephrine. 58
DRUGS CAUSING EJACULATORY DISTURBANCE
In our attempt to treat disorders such as hypertension or affect an improvement in the psychoneurotic or depressed patient, a variety of drugs are often used. Although each of these drugs can be beneficial as to its primary activity, secondary chemical or neurologic sequela may occur which impairs ejaculatory ability. 59-62 Table 2 lists commonly used drugs which may cause ejaculatory disturbance. Some of these may have antiadrenergic properties preventing complete closure of the bladder neck, others may inhibit emission of semen into the urethra, and still others, the psychotropics in particular, may cause retarded ejaculatory response with prolonged latency period between intromission and ejaculation. SPINAL CORD INJURY
Spinal cord-injured patients suffer a variety of sexual incapabilities dependent on the level of their spinal injury. Bors and Comarr,63 Comarr,64 and Comarr and Gunderson65 have succinctly detailed the sexual capability in a large series of patients. Those men with complete upper motor neuron lesions rarely ejaculated, although about 70% are capable of erection sufficient for intercourse. With incomplete upper motor neuron lesions, men exhibited a somewhat greater frequency of ejaculation. Very few men with complete lower motor neuron lesions were likely to achieve erection or ejaculate. With incomplete lower motor neuron lesions, the majority of men maintained an erection sufficient for intercourse, and about half of these retained their ability to ejaculate. If one considers all the men in these series, 450
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only 3% were able to achieve a pregnancy with their spouse. Due to the fact that there has been greater emphasis on the care and rehabilitation of the spinal cord-injured patient and consequent longer life expectancy, more of these men and women are interested in and capable of full and active lives, including marriage and offspring. 66 Since ejaculation does not occur in the majority of these patients, various methods have been proposed to stimulate these nerve-injured centers to cause emission and expulsion of sperm. 67 -71 Reports in veterinary medicine journals on the use of electrical stimulus to achieve ejaculation in animals began appearing in the 1930s. Ten to 15 years later, such stimulation was attempted in paraplegic men; but because of "electrical uncertainties" and fear of injury to the patient, this technique has never achieved any great degree of acceptance. Even with today's higher technology, although local injury can be avoided, the success in obtaining fertile sperm in this manner has been limited. Francois et al. 69 performed 116 electrostimulations, resulting in 63 ejaculations. Forty-two percent of patients ejaculated, and only one pregnancy occurred. Brindley 71 applied his modified technique to 84 patients, 50 responding either with antegrade or retrograde ejaculation. Again, only one pregnancy was achieved. One of the significant factors, with this and other techniques, is the potential occurrence of autonomic dysreflexia. Frankel and Mathias70 described the mandatory laboratory equipment as being a "cardiac arrest trolley" with various medications such as pentolinium, phentolamine, propranolol, and prostaglandin estradiol. Although outwardly appearing to be somewhat effective in obtaining sperm, the quality is usually not adequate, and the risks, particularly for those men with high spinal lesions, appear to outweigh the potential benefits. Due to the varied and incomplete lesions noted with spinal cord injuries, the occurrence of ejaculation is obviously uncommon. Sperm, if available at all, varies in quality and this quality appears to lessen with time from injury. Whether this is due to neurovascular changes or temperature-related phenomena is unclear at present. 72 -74 The use of the electrovibrator has met with some success in patients with various levels of spinal cord injuries. 68-75 Amelar et al. 76 have described a modification to the hand-held vibrator, allowing the semen to be ejaculated and collected Fertility and Sterility
individual patient with the use of a computer and a constant arterial pressure monitor. It is quite obvious that this method is not to be considered a "routine procedure" and should only be carried out where strict monitoring and immediate and appropriate therapy can be rendered. CONGENITAL CAUSES OF EJACULATORY ABNORMALITIES
Figure 2 Obstruction of the ejaculatory ducts. Note dilated, tortuous vas deferens emptying into the cystic structure (Mullerian duct cyst).
to be used for insemination. This technique has been found to be useful and safe but effective in only a few patients. Undoubtedly, the most interesting technique for achieving erection and ejaculation is that described by Guttman and Walsh 77 using intrathecal injection of neostigmine. Originally proposed in 1947, this drug has been shown to elicit erection and ejaculation in a large percentage of males. Single or multiple ejaculations were observed in approximately 60% of 70 men with complete upper motor neuron lesions and 75% of 29 men with incomplete upper motor neuron lesions. Two thirds of those men with complete lower motor neuron lesions failed to ejaculate. Two pregnancies were achieved by artificial insemination with homologous semen but ended in spontaneous abortions. Again, one of the major drawbacks with this technique is the incidence of autonomic dysreflexia, particularly in those men with high cervical lesions. Drugs must be immediately available for treatment. Lipshultz et al. 58 have recommended the use of Nitroprusside (Roche Laboratories, Division of Hoffmann-La Roche Inc., Nutley, NJ) to control this response. The drug is titrated to the Vol. 39, No.4, April 1983
Although uncommon, congenital absence of the vas deferens and seminal vesicles does occur, on either one or both sides. When unilateral, it is often associated with ipsilateral absence of the kidney, but the ejaculatory volume is usually normal. With bilateral absence of the vas, the ejaculated fluid volume is small, less than 1 ml, and acidic and, of course, contains no sperm. Children who are born with bladder exstrophy may have normal spermatogenesis; but in the attempt to reconstruct the bladder and urethra, the ejaculatory ducts may be obstructed or retrograde ejaculation may occur due to the absence of a competent bladder neck. 78 Young men with a corrected epispadias may have ejaculatory disturbances due to irregularity and/or stricture of the urethra as well as poor development of the muscles involved with semen propulsion through the urethra. Rarely, azoospermia and a small ejaculatory volume may be found due to a congenital obstruction of the ejaculatory ducts, which may empty into a Mullerian duct cyst (Fig. 2). In such a case, transurethral resection or unroofing may provide adequate drainage and consequent fertility.79, 80 FUNCTIONAL EJACULATORY DISORDERS
Premature ejaculation rarely affects fertility potential unless ejaculation occurs prior to vaginal penetration. The treatment of this common malady has been highly successful in the wellmotivated individual. 81 -83 Retarded ejaculation represents a significant problem for the couple trying to achieve a pregnancy. Most commonly, ejaculation is simply not possible during coital activity.84-86 Although initially thought to be a rare phenomenon, recent studies have shown an increase in the number of patients complaining of ejaculatory incompetence. Kaplan84 described an incomplete form of this problem where orgasmic sensation was intact but the semen would ooze from the urethra rather Thomas Ejaculatory dysfunction
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than be expelled vigorously by the contraction of the perineal musculature. There are a number of psychodynamic formulations to explain both premature and retarded ejaculation. Suffice it to say that if no organic cause can be found, appropriate counseling is indicated. If, in the case of retarded ejaculation, semen is able to be obtained by masturbation or electrovibration, artificial insemination by homologous semen can be carried out if the sperm quality is adequate. REFERENCES 1. Herberg LJ: The hypothalamic mechanism causing seminal ejaculation. Nature 198:219, 1963 2. Kimura Y, Kisaki N, Sakurada S, Tadano T: On the brain monoaminergic systems relating to ejaculation. I. Brain dopamine and ejaculation. Andrologia 8:313, 1976 3. Kimura Y, Kisaki N, Sakurada S, Tadano T: On the brain monoaminergic systems relating to ejaculation. II. Brain serotonin and ejaculation. Andrologia 9:50, 1977 4. Brueschke EE, Zaneveld LJD, Rodzen R, Berns D: Development of a reversible vas deferens occlusive device. m. Morphology of the human and dog vas deferens: a study with the scanning electron microscope. Fertil Steril 25:687, 1974 5. Anton PG, McGrath JC: Further evidence for adrenergic transmiBBion in the human vas deferens. J Physiol (Lond) 273:45, 1977 6. McLeod 00, Reynolds DG, Demaree GE: Some pharmacologic characteristics of the human vas deferens. Invest Urol 10:338, 1973 7. Baumgarten HG, Holstein AF, Rosengren E: Arrangement, ultrastructure, and adrenergic innervation of smooth musculature of the ductuli efferentes, ductus epididymis and ductus deferens of man. Zelforsch 120:37, 1971 8. Learmouth JR: A contribution to the neurophysiology of the urinary bladder in man. Brain 54:147, 1931 9. Davidson JM: Neurohormonal bases of male sexual behavior. In International Review of Physiology, Edited by RG Greep. Baltimore, University Park Press, 1977, p 225 10. MacLean PP, Dua S, Denniston RH: Cerebral localization for scratching and seminal discharge. Arch Neurol 9:485, 1963 11. Herbert J: The role of the dorsal nerves of the penis in the sexual behavior of the male rhesus monkey. Physiol Behav 10:293, 1973 12. Bors E, Comarr AE: Neurologic disturbances of sexual function. Urol Surv 10:191, 1960 13. Coman AE: Sexual concepts in traumatic cord and cauda equina lesions. J Urol106:375, 1971 14. Comarr AE: Sexual function among patients with spinal cord injury. Urol Int 25:134, 1970 15. Dail WG, Evan AP: Experimental evidence indicating that the penis of the rat is innervated by short adrenergic neurons. Am J Anat 141:203, 1972 16. Owman CH, Sjoberg NO: The importance of short adrenergic neurons in the seminal emission mechanism of rat, guinea pig, and man. J Reprod Fertil 28:379, 1972 452
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17. Sjostrand NO: The adrenergic innervation of the vas deferens and the accessory male genital gland. Acta Physiol Scand 65:257, 1965 18. Marberger H: The mechanisms of ejaculation. Basic Life Sci (Part B) 4:99, 1974 19. Ichijo S, Sigg C, Nagasawa M, Siraiwa Y: Vasoseminal vesiculography before and after ejaculation. Urol Int 36:35,1981 20. Mitsuya H, Asai J, Suyama K, Ushida T, Hosoe K: Application of x-ray cinematography in urology. I. Mechanism of ejaculation. J Urol 83:86, 1960 21. Guha SK, Kaur H, Ahmed AM: Mechanics of spermatic fluid transport in the vas deferens. Med BioI Eng Comput (continues Med BioI Eng) 13:518, 1975 22. Gallizia P: The smooth sphincter of the vesical neck, a genital organ. Urol Int 27:341, 1972 23. Kimura Y, Miyata K, Adachi K, Kisaki N: Peripheral nerves controlling the closure of internal urethral orifice during ejaculation. Urol Int 30:218, 1975 24. Kimura Y, Adachi K, Kisaki N, !se K: Role of alphaadrenergic receptor mechanism in closure of the internal urethral orifice during the ejaculation. Urol Int 30:341, 1975 25. Tanagho E, Smith DR: The anatomy and function of the bladder neck. Br J Urol 38:54, 1966 26. Koraitim M, Schafer W, Melachior H, Lutzeyer W: Dynamic activity of the bladder neck and external sphincter in ejaculation. Urology 10:130, 1977 27. Stockamp K, Schreiter F: Function of the posterior urethra in ejaculation and its importance for urine control. Urol Int 29:226,1974 28. Benson GS, Sarshik S, Raezer D, Wein A: Bladder muscle contractility: comparative effects and mechanisms of action of atropine, propantheline flavoxate, and imipramine. Urology 9:31, 1977 29. Gosling JA, Dixon JS, Lendon RG: The autonomic innervation of the human male and female bladder neck and proximal urethra. J Urol 118:302, 1977 30. Naomidis S: The physiology and pathology of the urinary bladder neck. Urol Int 27:393, 1972 31. Purohit R, Beckett S: Penile pressures and muscle activity aSBociated with erection and ejaculation of dog. Am J Physiol 231:1343, 1976 32. Peterson I, Stener I: The electromyographical study of the striated urethral sphincter, the striated anal sphincter, and the levator ani muscle during ejaculation. Electromyogr Clin Neurophysiol (continues Electromyography) 10:23,1970 33. Rieser C: The etiology of retrograde ejaculation and a method for insemination. Fertil Steril 12:488, 1961 34. Ochsner MG, Bums E, Henry HH: Incidence of retrograde ejaculation following bladder neck revision as a child. J Urol 104:596, 1970 35. Koraitim M, AI-Ghorab M: Normal ejaculation after YV urethrocystoplasty. Br J UroI42:462, 1970 36. Gute D, Chute R, Baron J: Bladder neck revision for obstruction in men: a clinical study reporting normal ejaculation postoperatively. J Urol 99:744, 1968 37. Sandler B: Idiopathic retrograde ejaculation. Fertil Steril 32:474, 1979 38. Keiserman WM, Dubin L, Amelar RD: A new type of retrograde ejaculation: report of three cases. Fertil Steril 25:1071, 1974
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39. Kedia KR, Markland C, Fraley EE: Sexual function following high retroperitoneal lymphadenectomy. J Urol 114:237,1975 40. Bracken RB, Johnson DE: Sexual function and fecundity after treatment for testicular tumors. Urology 7:35, 1976 41. Hermanek P, Siegel A: Necessary extent of lymph node dissection in testicular tumours: a histopathological investigation. Eur UroI8:135, 1982 42. Narayan P, Lange PH, Fraley EE: Ejaculation and fertility after extended retroperitoneal lymph node dissection for testicular cancer. J Urol 127:685, 1982 43. Weinstein MH, Machleder HI: Sexual function after aorto-iliac surgery. Ann Surg 181:787, 1975 44. Williams DI, Watson PC, Golligher JC, Riches EW, Gabriel WB, Pyrah LN: Discussion on urological complications of excision of the rectum. Proc R Soc Med 44:819, 1951 45. Abrahams JI, Solish GI, Boorhan P, Waterhouse RK: The surgical correction of retrograde ejaculation. J Urol 114:888, 1975 46. Mahadevan M, Leeton JF, Trounson AO: Noninvasive method of semen collection for successful artificial insemination in a. case of retrograde ejaculation. Fertil Steril 36:243, 1981 47. Crich JP, Jequier AM: Infertility in men with retrograde ejaculation: the action of urine on sperm motility, and a simple method for achieving antegrade ejaculation. Fertil Steril 30:572, 1978 48. Hotchkiss RS, Pinto AB, Kleegman S: Artificial insemination with semen recovered from the bladder. Fertil Steril 6:37, 1955 49. Fischer IC, Coats EC: Sterility due to retrograde ejaculation of semen: report of pregnancy achieved by autoinsemination. Obstet Gynecol 4:352, 1954 50. Thiagarajah S, Vaughan ED Jr, Kitchin JD ill: Retrograde ejaculation: successful pregnancy following combined sympathomimetic medication and insemination. Fertil Steril 30:96, 1978 51. Stewart BH, Bergant JA: Correction of retrograde ejaculation to sympathomimetic medication: preliminary report. Fertil SteriI25:1073, 1974 52. Kragt F, Schellen A: Clinical report of some cases with retrograde ejaculation. Andrologia 10:381, 1979 53. Hosking DJ, Bennett T, Hampton JR: Diabetic autonomic neuropathy. Diabetes 27:1043, 1978 54. Kolodny RC, Kahn CB, Goldstein HH, Barnett DM: Sexual dysfunction in diabetic men. Diabetes 23:306,1974 55. Odel lIM, Roth GM, Keating FR: Autonomic neuropathy simulating the effects of sympathectomy as a complication of diabetes mellitus. Diabetes 4:92, 1955 56. Rundles RW: Diabetic neuropathy: general review with report of 125 cases. Medicine (Baltimore) 24:111, 1945 57. Greene LF, Kelalis PP: Retrograde ejaculation in semen due to diabetic neuropathy. J UroI98:693, 1968 58. Lipshultz LI, McConnell J, Benson GS: Current concepts of the mechanisms of ejaculation: normal and abnormal states. J Reprod Med 26:499, 1981 59. Segraves RT: Male sexual dysfunction and psychoactive drug use: review of a common relationship. Postgrad Med 71:227, 1982 60. BUlpitt DJ, Dollery CT: Side effects of hypotensive agents evaluated by a self administered questionnaire. Br Med J 3:485,1973
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61. Ahlenius S, Heimann M, Larsson K: Prolongation of the ejaculation latency in the male rat by Thioridazine and Chlorimipramine. Psychopharmacology (Berlin) 65: 137, 1979 62. Innes IR, Nickerson M: Norepinephrine, epinephrine and the sympathomimetic amines. In The Pharmacological Basis of Therapeutics, Edited by LS Goodman, A Gilman. New York, MacMillan Publishing, 1975, p 477 63. Bors E, Comarr AE: Neurological disturbances of sexual function. Urol Surv 10:191, 1960 64. Comarr AE: Sexual function among patients with spinal cord injury. Urol Int 25:134, 1970 65. Comarr AE, Gunderson BB: Sexual function in traumatic paraplegia and quadraplegia. Am J Nurs 275:250, 1975 66. Masham B: The psychological and practical aspects of sex in the marriage for the paraplegic. Proc R Soc Med 66:133, 1973. 67. Rossier AB, Ziegler WH, Duchosal PW, Meylan J: Sexual function and dysreflexia. Paraplegia 9:51, 1971 68. Brindley GS: Reflex ejaculation under vibratory stimulation in paraplegic men. Paraplegia 19:299, 1981 69. Francois N, Maury M, Jouannet D, David G, Vacant J: Electro-ejaculation of a complete paraplegic followed by pregnancy. Paraplegia 16:248, 1978 70. Frankel HL, Mathias CJ: Severe hypertension in patients with high spinal cord lesions undergoing electro-ejaculation: management with prostaglandin E 2 • Paraplegia 18:293, 1980 71. Brindley GS: Electro-ejaculation: its technique, neurological implications and uses. J Neurol Neurosurg Psychiatry 44:9,. 1981 72. Brindley GS: Deep scrotal temperature and the effect on it of clothing, air temperature, activity, posture and paraplegia. Br J Urol 54:49, 1982 73. David A, Ohry A, Rozin R: Spinal cord injuries: male infertility aspects. Paraplegia 15:11, 1977 74. Higgins GE: Sexual response in spinal cord injured adults: a review of the literature. Arch Sex Behav 8:173, 1979 75. Tarabulcy E: Sexual function in the normal and in paraplegia. Paraplegia 10:201, 1972 76. Amelar RD, Dubin L, Walsh PC: Male Infertility. Philadelphia, W. B. Saunders, 1977; p 208 77. Guttman L, Walsh JJ: Prostigmin assessment test offertility in spinal man. Paraplegia 9:39, 1971 78. Hanna NK, Williams DI: Genital function in males with vesical exstrophy and epispadias. Br J Urol 44:169, 1972 79. Brooks RT: Cyst of the ejaculatory duct: case report. J Urol 101:881, 1969 SO. Furtado AJL: Three cases of cystic seminal vesicle associated with unilateral renal agenesis. Br J Urol 45:536, 1973 81. Masters WH, Johnson VE: Human Sexual Inadequacy. Boston, Little, Brown & Co., 1970, p 92 82. Semmens JP, Semmens FJ: Premature ejaculation and impotence: male problems with gynecologic implications. Clin Obstet Gynecol 21:223, 1978 83. Semans JH: Premature ejaculation: a new approach . South Med J 49:353, 1956 84. Kaplan HS: The New Sex Therapy. New York, a Brunner/Mazel Publication, Quadrangle/New York Times Book Co., 1974, p 319
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85. Munjak. DJ, Kanno PH: Retarded ejaculation: a review. Arch Sex Behav 8:139, 1979
86. Nininger JE: Inhibition of ejaculation at orgasm. NY State J Med 79:725, 1979
Received December 6, 1982. Reprint requests: Anthony J. Thomas, Jr., M.D., Head, Section of Male Infertility, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.
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