Vol. 11 4, October

THE JOt;RNAL OF UROLOGY

Copyright.© 1975 by The Williams & Wilkins Co.

Printed in U.S.A.

THE EFFECT OF PHARMACOLOGICAL AGENTS ON E,JACULATION KAILASH KEDIA AND COLIN MARKLAND From the Department of Urolo{?ic Sur{?ery, University of Minnesota Health Sciences. Minneapolis , Minnesota

ABSTRACT

Infertility in a patient on pharmacological agents with sym patholytic activity was found to be caused by ejaculatory failure owing to absent contraction of the seminal vesicle, ampulla and ductus deferens, rather than the previously accepted reason of retrograde ejaculation. These findings suggest that pharmacological agents producing alpha-adrenergic blockage may produce temporary interference with ejaculation, suggesting investigation of their use as reversible male contraceptives.

Since normal ejaculation depends upon the intact autonomic nervous system chemical sympathectomy can cause interference . Various pharmacological agents have been shown to effect the ejaculatory process but the exact mechanism has never been precisely explained.'· 2 In the past , several authors have asserted that sympathectomy disturbs ejaculation by causing bladder neck d ysfunction, allowing retrograde emission of semen into the bladder. a-, This thought led many to believe that drugs with sympatholytic action might also result in retrograde ejaculation. Recently, it has been shown that. there is no evidence of retrograde ejaculation following extensive surgical sympathectomy. • We evaluated a sma ll group of patients who had been on various pharmacologi cal agents with sympatholytic action and found that all patients were potent , a ll experienced normal orgasm but none had normal ejaculation. The results of our study suggest that loss of ejaculation in these patients is owing to reasons other than retrograde ejaculation. MATERIAL AND METHOD

presence or a bsence of norma l orgasm and ejaculation and 3) fructose studies before and after masturbation. Urine and semen were studied for fructose using the qualitative Selivanoffs fructose test ' in the following sequence : 1) preliminary urine examination-a fru ctose test was done on a freshl y voided specimen to ser\'e as a control to rule out abnormal presence of fru ctose prior to su bsequent testing, 2) semen sa mple-pa tients were requested to masturbate and any seminal specimen was immediately examined microscopically for sperm and for fructose using Selivanol'f's reagent. 3) post-masturbatory urinalysis-a voided urine sample immediately following masturbat ion was examined for sperm and fructose to determine the possible presence of semen within the bladder owing to re trograde ejaculation, 4) examination of prosta tic secretion- the prostate was t hen massaged, examining the secretions for sperm and fructose to determine the presence or absence of sperm dependent on ductus deferential peristalsis and seminal vesicular contraction and 5) post-prostatic massage urinalysis-this was examined for sperm and fru ctose to determine the presence or absence of sem inal vesi!'ular secretions.

From 1971 to 1974, 9 patients varying in age from 28 to :36 years a nd receiving sympatholytic agents RESULTS were evaluated. Seven patients had been receiving All patients reported norma l sexual function antihypertensive therapy with 50 to 100 mg. guanethidine* for 6 months to 3 years. Two pa- prior to therapy and none had had any noticeable tients had been receiving 25 to 50 mg. thioridazi ne problems related to ejaculation or orgasm. Pohydrochloridet for 1 to 8 months. The sexual fun c- tency, orgasm and frequency of coitus were estion evaluation included: 1) the type of pharmaco- sentially unchanged during therapy in all patients. logica l agent, duration and dosages of therapy; 2) Ejaculat ion was absent in all patients and they sexual function before and during the therapy, described having dry sex. There was no evidence of recording coital frequency, erectile ability, the retrograde ejaculat ion in any patient, examination of the post-masturbatory urine sample was connegative for sperm or fructose. Prostatic sistently Accepted for publication February 18 , 1975. Read at annual meeting of North Central Section, secret ions and post -prostatic massage urinalysis American Urological Association, Columbus, Ohio, Sep- showed neither sperm nor fructose . tember 18- 21, 1974. • Ismelin, Ciba Pharmaceutical Company, Summit. D1sn:ss10N New Jersey. Studies of the physiology of the ductu s deferens t Mellaril, Sandoz Pharmaceuticals, East Hanover, New ,Jersey. and seminal vesicle date from the work of Rudge ." S69

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KEDIA AND MARKLAND

He found that stimulation of the inferior mesen teric ganglion, the hypogastric nerve and the lumhar communi cantes produced contraction of the rabbit ductus deferens. Similar studies were continued by Loeb, Remy and Sherrington. •· ' ' Sherrington showed that stimulation of the 12th thoracic and the 1st, 2nd and :\rd lumbar nerves in the rhesus monkey and the :\rd and 4th nerves in the cat produced contraction of the ductus deferens. A most significant findin g was reported by Langley and Anderson in 1896 12 · 14 who showed that the ductus deferens and seminal vesicle nerve supply of the rabbit was from 2nd, :.~rd and 4th lum bar nerves. The nerve fibers were snown to run to the inferior mesenteric ganglion, from there following the hypogastrir nerve to the internal genitalia. They also demonstrated that pel vic nerve stimulation did not produce ductus deferens or seminal vesicular contraction. The preganglionic fibers to these organs were shown to relay via the inferior mesenteric ganglion a nd a lso in the peripheral gan glia a t the base of the seminal vesicle. These observations suggested that the hypogastric nerve was composed of preganglionic and post ganglionic fibers. In 19J8 Grundfest and Casser stated that the predominance of C fibers. with only few R fibers. in the hypogastric nerve was more tvpical of a postganglionic structure with relay via the hypogastric ganglia ." However, in 196fi Sjiistrand con firmed that the original observations of Langle:.: and Anderson were correct.'" The finding that many specific ganglionic blocking agents abolish the response of guinea pig duct us deferens to h:-,•pogastric nerve stimulat ion a nd sect ion of the hy pogastric nerve did not result in decrease of the noradrenaline content of the ductus deferens clearlv showed that the hypogastric nerve is a pregan gli onic structure. The finding also suggested that there is a synaptic relay close to the ductus deferens and seminal vesicle, short adrenergic neurons being the fin a l link in the innervat ion of duct us de!erens. am pulla. seminal vesicle and prostate (fig. ll. The te rm short adrenergic neuron was introduced by Sjiistrand to describe the final post-s:vn aptic sympathetic nerve supplying the interna l genitalia. This term was used to differentiate the final pathway from long adrenergic neurons with cell bodies in the prevertebral or paravertebral ganglia. Similar observations were also made in the stud ies of Bently a nd Sabine, Birmingham a nd Wilson, a nd Ohlin a nd Stromblad. 11 • 1• Besides the pronounced sympathetic inn ervation of t he ma le internal genitalia there is also some evidence of the cholinergic innervation . The studies using Hukovic's isolated guinea pig ductus deferens hypogastric nerve preparation showed some unexpected findings that did not correlate with classical concepts of adrenergic n eura l transmission. 20 Similarly, Boyd and associates showed that a lpha adrenergic blocking agents enhance rat her than inhibi t nerve-induced ductus deferens contractions. 21 They also demonstrated that choline

SYMPATHETIC NERVE SUPPLY TO INTERNAL MALE GENITALIA ~

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esterase-inhibitors potentiate nerve- ind uced contraction of the type, which can be blocked by atropine. These findings were supported by Burn and Rand, who suggested that a non-ganglionic cholinergic pathway was involved in adrenergic transmission. 22 However, recent electrophysiological, histoche mical and electron microscopical studies have established that innervation of the internal gen italia 1s predominantly adrenergic. ,s. 2J - 2s There have been limited studies on human ductus deferens and seminal vesicles . However, recent organ bath studies using human ductus deferens have shown dose-dependent excitatory responses, only to noradrenaline and adrenaline, again suggesting that motor innervation is a drenergic and operates through a lpha-adrenergic receptors. 27 PHYSIOL(l(;y OF EREC'TIOK. ORCASM AND E.JACCLATIO~

Erectile potency is controlled by the parasympathetic nerves or nervi erigentes . Parasympathetic activity produces vasodilatation of the penile arteries with occlus ion of the penile veins. causing engorgement of the cavernous bodies of the penis and urethra. Ejac ulatory cont rol is a separate process and relates to 3 discrete phenomena. These events are sem inal emission , ant egrade ejaculation and l)ladder neck closure. They are dependent on a reflex neural process (fig. 2l. In this reflex afferent sensor\ stim uli are initially relayed from the geni talia via the pudenda I nerve to the cerebral cortex.

EFFECT OF PHARMACOLOGICAL AGENTS ON EJAC ULATION

571

Physiology of

Ejaculation

THORA CO LUMBAR SPINAL GANGLIA (Tl2-L3) a.;---:ll~ Smooth muscle o ntra cti on of Pr os tat e, Semi nal Vesi cl e, Vas Defer ens Partial bla d der nec k clo sur e

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The efferent neural fibers travel through t he anterolateral columns to the thoracolumbar sympathetic outflow, emerging through the T l 2 to L 3 sympathetic ganglia. This sympathetic neural output controls smooth muscle contraction of the duct.us deferens, stimulating peristalsis with propulsion of semen from the cauda epididymis to the ampulla on ejaculation. Similarly, smoot h muscle contraction in the ampulla, prostate a nd sem ina l vesicle, with partial closure of the bladder neck, produces seminal emission in the posterior uret hra_ Further efferent neural control is medi ated through the parasympathetic sacral outflow, causing clonic contraction of the striated bulbocavernosus a nd ischiocavernosus muscles, which together with complete closure of the bladder neck, results in rhythmic projectile ejaculation t hrough the urethra. 28 Orgasm is a cortical sensory experience, with afferent neural input from contraction of the smooth muscles of the internal sex organs and the pelvic striated muscles. 29 This complex mechanism explains how pharmacological agents with sympatholytic action abolish seminal emission, without disturbing erectile potency or the sensation of orgasm. There are several reports in the literature describing the effect of guanethidine on ejaculation but the mech;inis m has never been extensively studied_ 3 u Bauer a nd associates suggested that impairment of sexual function in male subjects after guanethidine t herapy was s imila r to that observed after extensive lumbar sympathectomy, although the site and mechanism of action were not described_ 31 A possible explanation might be that mitochondria of n eurons damaged by guanethidine undergo gross ultrast ructu ral modi-

2

fication. It has been shown that 100 mg. per kg. guanethidine given 16 to 24 hours before sacnfice of rats results in complete depletion of cat echolamines in the adrenergic neurons of the duct.us deferens and seminal vesicles. 32 Evans and associates showed that chronic treatment of animals with low doses (5 mg. per kg.) of guanethidine for a long period damaged the short adrenergic neurons of the male reproductive tracts, although adrenergic nerves in other parts of the body were not seriously affected. 33 Histological, fluorescence histochemical and electron microscopic studies have also shown that guanethidine causes degeneration of sympathetic adrenergic neurons with a specific selective action of the short adrenergic nerves of the male reproductive tract. 33· " ' Recently. several reports have described the effect of psychoactive drugs on ejaculat ion _ Singh and Freyha n reported absence of ejacula tion in patients receiving thioridazine hydrochloride therapy_ 1. 35 Green and Berman re ported that retrograde ejaculation was caused by phenoxybenzamine hydrochloride therapy, although they did not describe how this observation was made. 2 T hese findin gs suggest that alpha-ad renergic blocking agents might affect contractility of the ductus deferens, ampulla and seminal vesicles so as to produce temporary aspermia. Bretylium, bethanedine a nd reserpine, previously alleged to cause infertility by retrograde ejaculation, should be st udied for their effect on ejaculation by producing alpha-adrenergic blockage. This suggests that drugs with s imilar temporary spec ific effects on smooth muscle contraction of the ductus deferens, am pull a and seminal vesicles might serve as reversible male rnntraceptives.

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KEDIA AND MARKLAND

REFERENCES

1. Singh, H.: A case of inhibition of ejaculation as a side effect of mellaril. Amer. J. Psychiat., 117: 1041, 1961. 2. Green, M. and Berman, S.: Failure of ejaculation produced by dibenzyline; preliminary report. Conn. Med .•J., 18: 30, 1954. 3. Greene, L. F., Kelalis, P. P. and Weeks, R. E.: Retrograde ejaculation of semen due to diabetic neuropathy. Fertil. Steril., 14: 617. 1963. 4. Rose, S. S.: Investigation into sterilitv after lumbar ganglionectomy. Brit. Med. ,J., I: 247, 1953. 5. Walters, D. and Kaufman, M. S.: Sterility due to retrograde ejaculation of semen. Amer. ·.J. Obst. Gynec., 78: 274, 1959. 6. Kedia. K. R.. Markland, C. and Fraley, E. E.: Sexual function following high retroperitoneal lymphadenectomy. J. Urol., 114: 2:n. 1975. 7. Hawk, P. B., Oser. B. L. and Summerson, W. H.: Practical Physiological Chemistry, l:3th ed. '.\iew York: McGraw-Hill Book Co .. pp. 7:-l, 848 and 1332, 1954. 8. Budge: Ueber de Centrum genitospinale des N. sympathicus. Virchows Arch., 15: 115, 18,58. 9. Loeb, L.: Beitrange zue Bewegung der Samenleiter. Dissertation Giessen, 1866. 10. Remy, C.: Nerf's ejaculatuers .•J. de l'anat. et physiol., 22: 205, 1886. 11. Sherrington, C. S.: Cited by Langley and Anderson. ia, 14 12. Langley, J. N.: On the regeneration of pre-ganglionic visceral nerve fibers. J. Physiol.. 22: 215, 1897. 13. Langley, J. N. and Anderson, H.K.: The innervation of the pelvic and adjoining viscera. Part IV: the internal generative organs. Part V: position of the nerve cells on the course of the efferent nerve fibers. J. Physiol., 19: 122, 1895-1896. 14. Langley, .J. N. and Anderson, H. K.: The innervation of the pelvic and adjoining viscera. Part VI: histological and physiological observation upon the effects of section of the sacral nerves. J. Physiol., 19: 372, 1895-1896. 15. Grundfest, H. and Gasser, H. S.: Properties of mammalian nerve fibers of slowest conduction. Amer. J. Physiol., 123: 307. 19:38. 16. Sjostrand, N. 0.: The adrenergic innervation of the vas deferens and the accessory male genital glands. An experimental and comparative study of its anatomical and functional organization in some mammals. including the presence of adrenaline and chromaffin cells in these organs. Acta Phvsiol. Scand., suppl. 257, 65: 1, 1965. • 17. Bentley, G. A. and Sabine, J. R.: The effects of ganglion-blocking and postganglionic sympatholytic drugs on preparations of the guinea-pig vas deferens. Brit. J. Pharmacol., 21: 190, 196:3. 18. Birmingham, A. T. and Wilson, A. B.: Preganglionic and postganglionic stimulation of the guniea-pig isolated vas deferens preparation. Brit. ,J. Pharmacol.. 21: 569. 1963. 19. Ohlin, P. and Stromblad, B. C.: Observations on the isolated vas deferens. Brit. ,J. Pharmacol.. 20: 299, 196:3. 20. Hukovic, S.: Responses of the isolated sympathetic nerve-ductus deferens preparation of the guineapig isolated vas deferens preparation. Brit. ,J. Pharmacol .. 21: 569. 196:3. 21. Boyd, H. , Chang, V. and Rand. M. J.: The anticholinesterase activity of some antiadrenaline

agents. Brit .•J. Pharmacol.. 15: 525. 1960. 22. Burn. ,J. H. and Rand, M. ,J.: Sympathetic postganglionic cholinergic fibres. Brit. ,J. Pharmacol.. 15: 56, 1960. 23. Richardson. K. C.: The fine structure of autonomic nerve endings in smooth muscle of rat vas deferens. ,J. Anat., 96: 427. 1962. 24. Yamauchi, A. and Burnstock. G.: Post-natal development of the innervation of the mouse vas deferens. A fine structural study. ,J. Anat., 104: 17, 1969. 25. Furness. ,J. B. and lwayama. T.: The arrangement and identification of axons innervating the vas deferensoftheguinea-pig.,J.Anat., 113: 179. 197:2. 26. Baumgarten, H. G., Falck, B.. Holstein, A. F., Owman, C. and Owman, T.: Adrenergic innervation of the human testis. epididymis. ductus defer· ens and prostate: a fluorescence microscopic and fluorimetric study. Z. Zellforsch., 90: 81. 1968. 2-1. McLeod, D. G .. Reynolds, D. G. and Demaree. G. E.: Some pharmacologic characteristics of the human vas deferens. Invest. Urol .. 10: :3:38, 197:,. 28. Semans, J. H. and Langworthv. 0. R.: Observations of the neurophysiology of ;exual function in the male cat. J. Urol.. 40: 8:36, 1938. 29. Kuntz, A.: The Autonomic Nervous System. Philadelphia: Lea & Febiger, 196f:,. · :30. Sah, H. ,J., Sah, P. P. and Peoples, S. A.: The new antihypertensive agent. guanethidine-a review. II. Clinic uses. dosage and routes of administration, side effects. important notes, summary, bibliography. Arzneimittelforschung, 16: 199, 1966. :n. Bauer, G. E., Hull. R. D .. Stokes. G. S. and Raftos, J.: The reversibility of side effects of guanethidine therapy. Med. ,J. Aust., I: 9:30. 197::l. 32. Evans, B., Iwayama, T. and Burnstock, G.: Longlasting supersensitivity of the rat vas deferens to norepinephrine after chronic guanethidine administration. ,J. Pharmacol. Exp. Ther .. 185: 60. 197:3. Evans, B., Gannon, B. ,J., Heath, ,J. W. and Burnstock. G.: Long-lasting damage to the internal male genital organs and their adrenergic innervation in rats following chronic treatment with the antihypertensive drug guanethidine. Fertil. Steril.. 23: 657, 1972. 34. Heath, ,J. W .. Evans. B. K., Gannon, B. ,J .. Burnstock, G. and ,James. V.: Degeneration of adrenergic neurons following guanethidine treatment: an ultrastructural study. Virchows Arch., 11: 182, 1972. :l5. Freyhan. F. A.: Loss of ejaculation during mellaril treatment. Amer. ,J. Psychiat.. 118: 171. 1961. COMMENT The well known effects of some adrenergic blocking drugs on human ejaculation are partially reviewed in this paper. The authors challenge the current opinion that this is the result of retrograde ejaculation. Unfortunately, the paper relates no data and one must rely on the authors· interpretation of their observations. I~ addition, there is no discussion on the recovery from drug effects and this has been of long duration· in the rodent. The interesting suggestion by the authors that these drugs may provide an approach to regulate male fertility merits additional studies. The main strength of the paper is in the review of the nerve supplv to the internal genitalia and the considerations releva~t to the effects of adrenergic blocking drugs on the mechanism of ejaculation. In light of the discussion in this paper.

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