Aspects of Genital Physiology and Pathology Gorm Wagner, M.D., Ph.D.

T h e function of the genitals as sex organs is highly related to the normal function of the individual in a biologic sense, but certainly also in relation to optimal age for offspring, to environmental influences, acute or chronic, and to internal emotional stability. As sexuality contains duality, being firmly linked to reproduction and to very private emotions (again sudden or persistent), the scientific investigation of the genitals has more or less been prevented by ethical considerations and moral standards, not least when it has come to studies that were not directly related to reproduction. Those who have dared to conduct such studies have usually been mature and well established in other areas of research. Many years ago, William H. Masters advised me, as George Corner had advised him "Get a tenured University position, pass the age of 40, and see that you're recognized in another field." I fbllowed this advice and have through the years experienced only minor (wellhidden) signals from my peer group that I am an outcast.

Such reasons, as well as personal hang-ups, may well explain the scarcity of studies of sexual function, especially within the medical field, which is conservative and represents the established social and cultural viewpoints of society. The true pioneer in understanding and describing the sex organs is not of our time. The Delft-based Dutch physician Regnier d e Graaf, who more than 300 years ago, under the protection of several European noblemen, elaborately described facts and phenomena almost inconceivable at that time, was a true investigator and clinician at the same time. Although he died at the age of 32, he managed to revolutionize large areas of anatomic knowledge, invent new instruments, and write several treatises on his discoveries and observations of female and male reproductive organs and their function. Not until 1972 were these complete works available, except in Latin.' After his death, however, darkness again fell on the study of genital organs and sexuality, in spite of the fact that this was at the early stage of the Enlightenment: it

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Institute of Medical Physiology, University of Copenhagen, Copenhagen, Denmark Reprint requests: Dr. Wagner, Associate Professor, Institute of Medical Physiology, Panum Institute University of Copenhagen, Copenhagen, Denmark DK-2200 N Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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erection and effectors of transport of spermatozoa and seminal emission. EFFECTORS OF PENILE ERECTION

The effectors of penile erection, controlled by the autonomic nervous system, are the smooth muscles of the penile arteries forming the inflow channels to the cavernous bodies (corpora cavernosa), the smooth muscle of the cavernous tissue, and the smooth muscle of the venous outflow, that is, the outflow system of the cavernous bodies. During penile erection, arterial dilation leads to MALE AUTONOMIC INNERVATION decreased resistance to inflow into the cavernous bodies; relaxation of smooth muscle in the cavernSince the latter half of the 19th century, the ous spaces, which allows increased capacity for autonomic nervous system has been known to play storing blood; and, in species having a retractor an important role in the functions of the male and penis muscle, muscle relaxation and protrusion of female reproductive system. (For reviews of older the literature, see Sjostrand,* Klinge and S j o ~ t r a n d , ~ Andersson et a18 studied penile erection folL e ~ i nand , ~ de Groat and S t e e n 5 During the last lowing pelvic nerve stimulation in the dog. They decades, there has been an increased interest in the found two main circulatory effects. First, there was subject. a prompt dilation of penile "resistance vessels," The autonomic nervous system is usually di- which increased the arterial inflow to the penis. In vided into the sympathetic and the parasympa- the early phase the cavernous bodies were bythetic systems. Originally, this division into two passed, so that venous outflow was increased to the parts was used for functional and morphologic rea- same extent as arterial inflow. After a delay, the sons. Since our view of the sympathetic and para- erectile response began, apparently as a result of sympathetic nervous systems as two opposing sets opening "low-resistance vessels" and diverting flow of nerves has changed as a result of increased into the cavernous bodies, which were then rapidly knowledge, it is now generally accepted that the filled. During filling of the cavernous bodies, arterms should be used as purely anatomic descrip- terial inflow exceeded venous outflow, but retions: the sympathetic nervous system is the tho- turned to the previous outflow level again in the racolumbar outflow of the autonomic nervous sys- steady state of full erection. Threshold frequency tem and the parasympathetic nervous system is the of stimulation was 1 to 2 Hz for the first response craniosacral outflow. and 1 to 4 Hz for the second response. Sympathetic fibers to pelvic organs leave the One objection can be made to the experimencentral nervous system through the lower thoracic tal setup of these studies. The authors cannulated and lumbar nerve roots. They reach the pelvic or- the deep dorsal veins which, in the dog, drain the gans by two main paths: via the ganglia of the sym- glans and corpus spongiosum, whereas the corpathetic chain, the paravertebral ganglia, and via pora cavernosa (with the erectile tissues) are the abdominal plexus, the prevertebral ganglia. drained by the cavernosal veins leaving at the crura The fibers of the first path have their synaptic re- of the corpus cavernosum. As has been pointed out lays essentially in the paravertebral ganglia. Post- earlier, there is a decreased blood flow rate in the synaptic fibers reach pelvic viscera via the puden- corpus cavernosum in man during full erection," dal and pelvic nerves or may just follow blood whereas the blood flow rate of the corpus sponvessels all the way. Mosi fibers of the second path giosum and glans is increased during the whole pehave their synaptic relays close to the target organs, riod of erection."' These effects may be similar in in terminal ganglia,2.5.6but some relay in paraver- animals that, like man and dog, have a "vascular" tebral o r prevertebral ganglia. The parasympa- penis with smooth muscle in the cavernous spaces thetic fibers run in the pelvic nerves. Their syn- and small arterial branches leading to the spaces: In the rabbit, the erectile response following pelvic aptic relays are in local (terminal) ganglia. It is convenient to discuss the autonomic ner- or hypogastric nerve stimulation consists of an inivous system and describe its actions by grouping its tial phase of slow increase in penile volume, foleffector cells according to their gross function. lowed by a phase of rapid volume increase, which This gives two main groups: Effectors of penile levels off once the penis becomes filled with blood.' 88

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was also a period that, after the discovery of the Americas, brought venereal diseases into a hitherto healthy and supposedly quite "free" sexual behavioral pattern. Gradually, through animal experiments and detailed studies of cells without any "sexual overtones," the study of the sex organs and reproduction has slowly become a natural part of our understanding of biologic functions and malfunctions.

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(;ENITAI. PHYSIOLOGY A N D PATHOLOGY-WAGNER

Myogenic Activity T h e term "myogenic tone" does not clearly explain the phenomenon: tone actually means a sustained state of contraction and says nothing about the cellular mechanisms involved; myogenic indicates that the origin of the tone is within the muscle itself, with no involvement of nerves, hormones, or specific transmitters. Tone may occur as a graded contracture when all cells are involved at the same time, giving rise to something similar to fused tetanus. However, a changing, asynchronous, phasic contraction pattern in many separate cells may also give rise to a tonic contraction, which may or may not look like a smooth tetanic contraction. This last phenomenon is known to occur in the microcirculation, in which a vessel at one time is closed and the next is

open, but still with the result that the total organ perfusion under resting conditions is kept constant. In the penis we find a structure that may imply that the primary resistance vessels in the arterial tree (the helicine arteries) function in this way. Their thick walls could serve for the purpose, and there is rich innervation at the very end of the vessel, which is budlike because of the heavy internal muscular cushions present there.".12 However, so far, no experimental procedures have been developed to study the functional and presumably regulatory behavior of these vessels. To describe this regulatory function of the resistance vessels in man new experimental techniques are much needed if we are to understand fully the perfusion of the normal penis and the implications of any pathologic changes. Little doubt exists as to the influence of pharmacologic agents on these specific structures, which are the location of relatively massive quantities of neurotransmitters. T h e cytoplasmic concentration of free calcium regulates the contraction of the cell. T h e smooth muscle cell is, however, dependent on the presence of external calcium, since an induced contraction can be maintained for only a few minutes in a calcium-free medium in an organ bath. T h e quick contractile response of the striated cell to an electrical stimulus ( 1 msec) is due to a rapid delivery of calcium to the contractile filaments, exclusively from the intracellular sarcoplasmic reticulum. In contrast to this, the transport of calcium across the smooth muscle cell membrane and into the contractile elements results in a considerably slower response (seconds). Intracellular mechanisms are able to prevent the tendency for intracellular Ca concentration to increase, partly by uptake into the sarcoplasmic reticulum and mitochondria and partly by extrusion of calcium. Lack of detailed knowledge of the vascular events leading to penile erection has created some confusion regarding nomenclature. For example, the term "shunt vessel" has been applied to vessels supposed to shunt blood away from the cavernous bodies. It seems likely, however, that in man, as in other species, dilation of vessels leading to increased arterial pressure and blood flow into the erectile tissue, as well as relaxation of smooth muscle in the trabeculae and walls of the erectile tissue, is the essential event in ere~tion.l"-'~

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I he decrease in penile volume following stimulation of' the sympathetic chain also had two phases, an initial rapid phase during which most of the volume decrease occurred and a later slow phase. T h e first phase had a maximum with stimulation at 4 Hz and the second at 8 to 16 Hz. T h e investigators suggested that the first phase of volume decrease was due to expulsion of blood from the penis, arising from contraction of the smooth muscle in the walls and trabeculae of the erectile tissue. T h e second phase was interpreted as an emptying of the erectile tissue because of greater resistance in the inflow than in the outflow vessels from the cavernous bodies. A common feature of many smooth muscle organs such as gut, myometrium, and ureter is the spontaneous activity that occurs and can be studied once the tissue has been placed in an organ bath. This spontaneous activity, which is seen in cavernosal smooth muscle tissue as well, is unaffected by tetrodotoxin, atropine, or phentolamine, and thus is myogenic. All of the organs mentioned, however, may have a superior regulator-the nervous system-to coordinate their function in vivo. Certain organs also may have pacemaker areas that, as in the heart, may exert a certain control on the rhythm. T h e difference is that no specific pathway like the conduction system of the heart exists in smooth muscle tissue, with the possible exception of the intestine. T h e tissue that most resembles the corpus cavernosum in function is the arterial resistance vessel. Local autoregulation governs the perfusion of some areas of the body (the pial vessels and kidney, for example); such autoregulation is due in part to pressure changes and in part to humoral factors. ?.

Electrical Activity of Smooth Muscle In rabbits, smooth muscle has been transplanted and grafted into a previously-inserted ear 89

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chamber.19Corpus cavernosum smooth muscle has sympathetic cholinergic vasodilator nerves in skelbeen grafted into an ear chamber containing plat- etal m ~ s c l eAndersson .~ et a18found in the dog that inum electrodes and has been found to have spon- atropine had no significant effect on pelvic nervetaneous electrical activity. Spike potentials on the induced blood flow in the penis but that it clearly order of 0.5 to 1.5 mV with a duration of 50 to 150 reduced the erectile response. These findings inmsec have been re~orded.'~.'~ dicate that the pelvic nerve-induced dilation of Studies in normal young men, using a unipo- minute vessels leading into the cavernous spaces lar electrode placed in the corpus cavernosum in has a cholinergic component. In isolated human the flaccid and erect states, showed that when the erectile tissue and penile vessels, muscarinic drugs penis is flaccid, electrical activity is nonsynchron- have been shown to induce r e l a ~ a t i o n . ' ~ - ~ ~ ous and scattered. Electrical activity of the corpus The description of an endothelium-derived cavernosum (EACC) diminishes significantly dur- relaxing factor (EDRF), by Furchgott3' in 1983 has ing visual sexual stimulation that leads to erection. definitely changed our view as to the messenger If an erection is induced pharmacologically, the pathway signaling a relaxation response of the electrical activity will disappear. If the erection is smooth muscle of vessels. Corpus cavernosum was sustained, EACC is still relatively low, but as soon included in studies that showed that a normal enas any disturbance in sexual stimulation occurs, dothelial lining was a prerequisite for the relaxaand before volume decreases, electrical activity in- tory effect of a~etylcholine.~~ Nerve terminals close creases, reaching its highest during the late detu- to endothelial cells have subsequently been demmescence phase.".'"urther clinical studies apply- onstrated. This finding provides the morphologic ing this method indicate that impotence due to basis for direct neural regulation of the endotheneural damage from radical surgery may be rec- lium.I2 ognizable in its smooth muscle electromyographic The EDRF system has been shown to involve (EMG) patterns. Since it seems to be the only nitric oxide (NO), which is a small, lipophilic molmethod available to study autonomous regulation ecule that diffuses easily through cell membranes locally, it is certainly important: discrete damage to to reach intracellular structures in cells near to the neural pathways leading to the penis is almost im- endothelial cell in which it was produced and repossible to detect objectively. However, no con- leased. NO links to the heme group of guanylate trolled large series have convincingly been pre- cyclase and causes a dramatic enzyme activation, sented and the method should be considered which results in biosynthesis of cyclic guanylate e~perirnental.'~-'" monophosphate (c-GMP) and thereby relaxation mission involved in erection is cholinergic. This of the smooth muscle.34In vitro formation and rehas been questioned because several studies have lease of NO and c-GMP have been demonstrated shown lack of effect of antimuscarinic drugs on by functional blockade of the adrenergic and choerection and weak or even contractile effects of linergic systems and by electrical field stimulation. muscarinic drugs on the effectors of penile erec- T h e phenomenon was blocked by tetrodotoxin, intion.7,27.2s There is, however, evidence in favor of dicating that a functional endothelium may not be cholinergic nerves playing a certain role in penile obligatory but rather that nonadrenergic, nonchoerection. The dilator response of the selectively linergic (NANC) neurotransmission leading to perfused penile artery of the rabbit obtained by generation of NO is required.35In an in vivo rabbit hypogastric nerve stimulation could still be de- model abolishment of penile erection elicited by creased and even abolished by scopolamine in cavernosal nerve stimulation by intracavernous insome experiments. After the acetylcholinesterase jection of an NO-synthesis inhibitor was possible.36 inhibitor neostigmine was added, the response These intriguing findings in very recent years have reappeared. Acetylcholine also produced a dilator brought us closer to a situation in which it is posresponse. The dilatory response to pelvic nerve sible, methodologically, to study the effects of new stimulation was, however, not significantly de- compounds in the search for specific mechanisms creased by scopolamine. T h e frequency-response that can be targeted by pharmacologic intervenrelationship between penile volume and stimula- tion. tion of the hypogastric nerve showed a maximum at 8 to 6 Hz-that is, at a frequency similar to that of cholinergic vasodilator nerves in skeletal muscle Adrenoceptors (18 to 20 Hz). The frequency-response relationship between penile volume and stimulation of the A h l q ~ i s tin~ ~1948 originally described a-repelvic nerves had its maximum in the range of 1 to ceptors on the basis of their pharmacologic recep2 Hz, which is much lower than that reported for tivity, dividing them into a and f3 types. T h e drug 90

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specificity, rather than the anatomic character, of or in the presence of a calcium antagonist, endoththe receptor was explicitly defined. Later division elin is able to contract the muscle, most probably of the p type into two subtypes, P, and P,, led to through the release of intracellular calcium and an the recognition that the properties of each type are increased sensitivity to calcium in the contractile intrinsic to the receptor gene products3* and that elements.45 It has been found that the penile vascular bed both may coexist on the same cell and within the participates in several general cardiovascular resame t i ~ s u e . ~ " The smooth muscle of the penile artery and flexes and responses such as baroreflexes, cardiac the cavernous trabecular tissue is richly inner- loading, respiratory reflexes, and reflex adjustvated. Comprehensive studies substantiate the ad- ment to bleeding.7 That the medullary neuron renergic system as the principal controlling system, pool responsible for penile vasomotor tone parat least in keeping the penis flaccid. The density of ticipates in general reflex cardiovascular homeothe a-receptors has been estimated at tenfold that stasis may have implications for normal erectile of the P-receptors and a, has been estimated at responses. Since vasoconstrictor nerves strongly over vasodilator nerves when both are si~-~* tenfold that of a, in the trabecular t i s s ~ e . ~ ' . ~ dominate However, Hedlund and Andersson" found the multaneously stimulated, a small increase in vasoa,-agonist clonidine to be more potent than nor- motor tone may make erection almost impossible. epinephrine when they studied the human caver- This may be one mechanism of erectile failure in nosal artery. This observation is crucial when we anxious men. evaluate new compounds that may be effective in inducing a pharmacologic erection in man, even more so because it has become clear that the a , Relaxation of Cavernosal Smooth Muscle type adrenoreceptor may be divided into subtypes and that certain compounds selectively block these Because relaxation of smooth muscle (cavernsubtype receptors.43In order to treat a pharmacoous trabecular muscle and the arterial system of logically induced, prolonged erection it is necesthe penis) is a prerequisite for erection, theoretisary to appreciate such differentiation. Recently, the contraction of smooth muscles in cally, any substance that relaxes smooth muscle the vascular system has been shown to be elicited should be able to induce erection. Papaverine was by endothelin, a 21-amino acid polypeptide, de- the first compound used clinically for this purIts mechanism of action remains unclear. rived and produced in the endothelium lining the pose.46,47 trabecular tissue. Cultures of endothelial cells from The problem in clinical use has been the route human corpus cavernosum have shown ability to of administration, because oral or intramuscular express endothelin mRNA. A high receptor affin- administration would also cause smooth muscle ority to plasma membranes and a dose-dependent gans in other areas to relax. By local intra-arterial contraction of in vitro smooth muscles strips have injection during surgery or arteriography, it apbeen demonstrated. The contractile effect of en- peared to be possible to obtain tumescence of the dothelin is different from norepinephrine in vitro, penis. Even better results were obtained by direct because its effect is sustained and cannot be injection into the cavernous body, which is now washed out, but can be reversed (relaxed) by ace- used as a diagnostic as well as a therapeutic meatylcholine, vasoactive polypeptide (VIP), or car- sure involving papaverine or the combination of bachol added to the bath.44 papaverine and p h e n t ~ l a m i n e . ~ ~ In studies in humans, Brindley4' examined In a recent discussion of the subject based on experimental work, H ~ l m q u i s twas ~ ~ unable to seven drugs that are known to relax smooth muscle demonstrate a clear localization of endothelin in by various mechanisms of action (phenoxybenzathe corpus cavernosum of rabbit and man by mine, phentolamine, thymoxamine, imipramine, immunohistochemical methods. However, a high verapamil, papaverine, and naftidrofuryl), all of density of binding sites was observed in the penile which caused erection when injected intracaverartery in both species. The absence of localization nously. Salbutamol, hydralazine, lidocaine, and buindicates that no intracellular stores exist in the tra- pivacaine induced tumescence, but not erection. becular tissue, but that binding sites do exist. All Metaraminol and guanethidine caused shrinkage together, this suggests that endothelin may play a followed by tumescence. Neostigmine, atropine, role in the normal penile erectile cycle. The con- propranolol, and idazoxan had no effects. Hence, tractions induced by endothelin are mainly depen- by direct relaxation of smooth muscle with papavdent on the existence of extracellular calcium. erine, by a mechanism still not ascertained, and by However, even in the absence of external calcium blocking of a,-receptors, it is possible to induce 91

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erection. T h e highly selective a,-blocker idazoxan the papaverine solution (pH 2.5 to 3.0), or to did not cause any erection, as was also the case with chemical disturbances provoked by the alcohol solocal application of yohimbine, a less selective a,- lution in which PGE, is dissolved. Long-term folblocker. low-up of such cases is not yet available. In clinical use, prolonged erection may follow T h e effect of oral intake of pharmacologically pharmacologically induced erection. Such cases active compounds that are prescribed for a pathoshould be dealt with within a few hours after the logic condition that is unrelated to sexual functions occurrence and can be treated by intracavernosal is difficult to evaluate. If a complaint of erectile injection of an a-adrenoceptor agonist or norepi- dysfunction follows such administration, this could n e ~ h r i n eIn . ~clinical ~ practice, the pharmacologic be due to changes in the underlying pathologic induction of erection may be useful in diagnostic condition, direct effect of drugs on mechanisms inprocedures and for therapeutic purposes. In some volved in penile erection, indirect effect mainly by cases, the patient himself can administer the intra- cerebral mechanisms, changes in environmental cavernous injection. For diagnostic purposes, doses (psychosocial, sexual) conditions, or a new pathoof papaverine ranging from 8 to 120 mg have been logic condition that may have occurred. This suggested for intracavernosal i n j e ~ t i o n ,some~ ~ , ~ ~ makes the study of drugs and sexual function comtimes combined with vibration or (VSS).51T h e aim plicated and requires control groups, double-blind, has been to evaluate the time to develop tumes- crossover studies, and an objective measure of the cence and rigidity and to evaluate the final results, degree of erection obtainable. Such studies are alfor it is difficult in a clinical setting to induce an most nonexistent. In one controlled study, atroerection using vibration or VSS alone.'' T h e re- pine, propranolol, and phenoxybenzamine were sponse of the arteries is evaluated using various given orally in clinically used doses to a group of Doppler techniques. Some cases of arteriogenic er- normotensive, healthy men who were able to demectile failure may benefit from periodically in- onstrate an erection under regular laboratory conduced erections at 4- to 6-week intervals. Injection ditions. It was found in these acute experiments is performed in the office; 60 to 80 mg of papav- that the ability to obtain and maintain an erection erine is given intracavernosally. was unchanged. It is now rather common for patients to give Since almost all antihypertensive drugs seem themselves injections in preparation for coital ac- to have been reported as causing erectile dysfunctivity. T h e dose of papaverine, with or without tion, one might wonder if a change in the hemophentolamine, necessary to produce an erection dynamics of the penis might not be a major factor has to be carefully titrated before the patient starts in such events. With our present knowledge, it this practice. For a comprehensive clinical discus- would seem theoretically possible that any comsion on the medical and psychologic aspects of this pound that has an adrenergic, serotonergic, hissubject, see Wagner and K a ~ l a n . ~ ~ taminergic, or prostaglandin F,,-like effect might More than 70,000 self-injections in more than have a direct effect on smooth muscle by inhibiting 3500 men have been reported. The incidence of relaxation. prolonged erections on self-injection programs is less than 0.5% regardless of whether papaverine is ElTECTORS OF SEMINAL EMISSION used alone or combined with phentolamine or prostaglandin E l (PGE,). Effectors of transport of spermatozoa and Comparisons of effectiveness of the various emission of semen include the smooth muscles of drugs have shown that papaverine alone induced the testicular capsule, excretory ducts of the testis erection in 36% and in combination with phentol- (ductuli efferentes, ductus epididymidis, vas defamine in 68%; in the same group of patients 76% erens, and ejaculatory ducts) and smooth muscle in had a full erection induced by PGE,."' U p to 20% the walls of the male internal accessory glands of men experience pain from' prostaglandin injec- (seminal vesicle, ampullary glands, prostate, and, tions. This can be alleviated by dilution or by re- in part, bulbourethral glands). T h e internal bladducing the amount of PGE, and adding phentol- der sphincter might be included in this group beamine. Some naturally occurring substances such cause it has similar innervation, and its contraction as calcitonin gene-related peptide or VIP also exert prevents retrograde emission.56 Reviews on these an erection-inducing effect when injected intracav- smooth muscles and their innervation have been ern~sally.~~.~~ p ~ b l i s h e d . ~The ' effectors of seminal emission reRepeated injections into the corpus caver- ceive a preganglionic nerve supply via the hyponosum may result in fibrotic changes due partly to gastric nerves. They are abundantly innervated by mechanical interference, partly to the low pH of adrenergic terminals derived from "short adren-

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demonstrated that the striated muscles did not contract during the development of erection. The participation of these muscles in erection had earlier been thought to be part of this function. Once penile erection, which now can be clearly defined as a purely vascular phenomenon, has occurred, however, and intracavernosal pressure has risen to equal mean arterial pressure, a further increase can be obtained by contraction of the two striated muscles. The pressure obtained in this way may approach 400 mmHg during the period of full voluntary contraction of the ischiocavernosus and bulbocavernosus muscles. If pressure cannot be maintained, it is a sign of abnormal drainage from the cavernous bodies; if it cannot be obtained, it is a sign of weak muscles. The bulbocavernosus reflex (BCR) is a bilateral, spinal, somatic reflex mediated through the pudendal nerve with reflex center in the second and third cord segment. T h e reflex is elicited by squeezing the glans between two fingers. The response is contraction of the bulbocavernosus muscle and the external anal sphincter. In normal men it has a latency of 30 to 40 msec. The value of this examination in impotent men as a diagnostic tool is much disputed, especially because prolongation of the latency period can be found in men without erectile failure and in impotent men who may have other than neurologic causes for their impairment. However, the reflex may be of importance under natural circumstances, because the pressure on the glans at the very moment of vaginal intromission may cause contraction of the striated muscles and thereby increase the intracavernosal pressure (that is, rigidity of the penis) momentarily in order to support entrance of the penis into the vagina.

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ergic neurons."58 Mixed with the adrenergic nerves are acetylcholinesterase-positive nerves. The dense innervation starts in the tail of the epididymis and reaches all effectors of seminal emission, which in general have strong muscular coats. In the bulbourethral glands the layer of smooth muscle is thin but these glands are enclosed by striated muscle. The smooth muscle appears usually to be relaxed unless activated by neuronal discharges. The human vas deferens is, however, capable of automatic it^^^ (automaticity is prominent in the contractile cells of the first parts of the excretory ducts, which have no strong innervation and therefore presumably are not governed by automatic nerve cells). A direct inhibitory innervation of the smooth muscle is apparently not present; only excitatory nerves appear to innervate the smooth muscle cells. It is, however, possible that cholinergic nerves may act as indirect inhibitory nerves via prejunctional suppression of the excitatory adrenergic nerves.60 There has been a debate concerning neurotransmission in the vas deferens. Adrenergic neuron blocking agents such as guanethidine block excitatory transmission, but in many species the initial response to nerve stimulation is not blocked by a,-adrenoceptor blocking agents. This resistance may be due to differing degrees of "intimacy" of the neuroeffector j ~ n c t i o n s . ~Hedlund ' et aF2 concluded that neurotransmission in the human vas deferens is adrenergic and mediated via a,-adrenoceptors. Furthermore, Wagner and BrindleyZ8found that oral administration of the a,-blocking agent phenoxybenzamine completely blocked ejaculation, although there was contraction of striated muscle at the same time that the subject experienced the sensation of orgasm. Since no sperm was found in the urine after this event, it can be concluded that the first part of ejaculation (internal emission) can be blocked by this compound. The external expulsion of semen, ejaculation proper, is maintained through a series of contractions (4 to 8 at 0.8 sec intervals) by the ischiocavernosus and bulbocavernosus muscles. A recent investigation'" with EMG recordings from both these striated muscles before, during, and after ejaculation demonstrated that within 1 second after the first contraction, the first spurt of semen occurred. After the last spurt, contractions continued up to 30 minutes but, often, as more tonic activity. In the same study, the EMG was recorded when the penis was still flaccid and during tumescence and full erection. In the normal young men who were the experimental subjects it was clearly

AUTONOMIC INNERVATION OF FEMALE GENITALIA The vagina and uterus are innervated by the sympathetic system through the pelvic part forming the plexus uterovaginalis, as well as by nerves derived from S2-4. The plexus is situated in the parametrium lateral to the cervix and the upper part of the vagina, and sends branches that follow the course of the vessels. On the anterior surface of the vagina, the plexus cavernosus of the clitoris innervates the clitoris and surrounding tissue. As pointed out by Levin: experiments employing nerve stimulation of the female genitalia have not been performed. No data have been obtained in females with spinal cord injuries with regard to reflexes and genital responses. 93

The immediate vaginal response to sexual stimulation is increased vaginal blood flow, followed by transudation of fluid onto the surface of the vagina and swelling of the clitoris." Although fluid production in the resting state and during sexual excitement is hormone-dependent, quantitative changes apparently d o not occur during the menstrual cycle. Only estrogen deprivation dramatically changes this pattern, because the number of subepithelial vessels and endothelial cells of the vagina decreases. There are no studies on the effect of estrogen on innervation. However, the threshold to vibration is decreased before postmenopausal women begin estrogen treatment. In a study of female volunteers, Wagner and Levid4 gave atropine and methylatropine in large therapeutic doses and studied the effect on vaginal blood flow and on subjectively reported orgasmic response to sexual self-stimulation. There were no changes (decrease or increase) in vaginal blood flow response to clitoral stimulation or orgasm. We interpreted this to signify that cholinergically mediated innervation, if it exists at all, is atropine-resistant and does not behave like an effector system with classic muscarinic receptors. Vaginal vascular response to vibratory stimulation of the clitoris was recorded by a photoplethysmographic method in a study by Gillan and Brind l e ~ They . ~ ~ found that the response could easily be repeated and occurred throughout the vagina but with the greatest amplitudes in its lower anterior wall and with varying latency (2 to 3 sec) but cumulatively over 30 seconds or more. Vibratory stimulation (80 Hz) of the clitoris also caused a sustained reflex contraction of the striated muscles of the pelvic floor. T h e authors regard this response as a tonic counterpart of the phasic BCR seen in the male. This is an example of a somatosensory afferent pathway having motor effects in both the somatic system and the autonomic system. During rest, there appear to be very few contractions of the smooth muscle of the wall of the vagina.'j6 T h e pressure increases observed during orgasm are due to contraction of the striated muscles surrounding the vagina. In a study by Zacur et aI6' it was found that intravenous injection of 500 p,g of thyrotropin-releasing hormone (TRH) induced pressure increases in both the urethra and the vagina, caused by contraction of the smooth muscle of these organs. Furthermore, in a TRH study by Levin and Wagner,66 seven of nine subjects experienced transient vaginal warmth, and, concomitantly, there was a significant increase in the blood flow of the vagina. In order to assess whether this was due to a central o r peripheral mechanism, TRH was administered as a bolus in94

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jection into the arterial supply of the vagina in anesthetized ewes. The injection induced a definite increase in vaginal blood flow and urination. In a recent review Levin" discusses the evidence for the involvement of VIP in vaginal vasodilation, which is a prerequisite for vaginal lubrication. VIP is present in nerves closely applied to blood vessels in the vaginal wall, and administration of VIP systemic or locally by subepithelial injection increases vaginal blood flow and induces vaginal fluid production. Another peptide, peptide histidine isoleucine has been demonstrated to be colocalized with VIP6%nd peptide histidine methionine has been found to increase vaginal blood Although the question has not been completely clarified, it seems justifiable to assume that vaginal vasodilation in response to sexual stimulation is NANC dependent and that VIP is most likely the major transmitter. Deficiency in vaginal lubrication is known clinically as a complaint from diabetic and postmenopausal women as well as in cases in which there is insufficient sexual stimulation during foreplay. The pathophysiology in diabetic women is unknown; the postmenopausal problem is caused by lack of estrogen, to be treated either by a vaginal lubricant or, more rationally, by local application of estrogen. Recently, a new tablet for vaginal use formulated to give a slow release has been marketed. The amount of estrogen necessary to change the vaginal mucosa into a well-functioning tissue is so small that no systemic estrogen effects occur. Another sexual complaint occurring in women is vaginism. This is, most likely, always a psychosomatic condition. It can occur as a primary or secondary phenomenon in women who, for known or unknown reasons, are phobic about vaginal penetration. The spastic contraction of all components of pelvic striated muscles including the perivaginal muscles is an involuntary reflex that can be induced by fantasy, anticipation, or an actual attempt to enter the vagina, be it with an instrument, a finger, or the penis. The incidence of the condition is unknown and, according to Kaplan," exploring the role of the unconscious has little relevance to treatment. Behavior therapy combined with manual stress-tension reduction treatment seems to be the most efficient and quick way to alleviate the condition. CLITORIS

In a histologic study in sheep of the nerve fiber content of the nerve to the clitoris, over 4000 fibers could be counted on each side. Comparison with the corresponding nerve in the male sheep,

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the dorsal nerve to the penis, in which only 2000 fibers could be counted, shows the abundance of the sensory innervation of the lito or is.'^ Conduction of impulses from the clitoris and neighboring regions of the vestibule to the spinal roots of S2, 3, and 4 was investigated in cats73and sheep.74Bipolar electrodes stimulated the sensory end organs. Cross-reflexes were found at the level of the third and fourth sacral segments, which are related to genital function. No physiologic or pharmacologic studies of the tumescence of the clitoris brought about by sexual stimulation have been published. It should be recalled that the clitoris is the homolog of the penile cavernous bodies. These structures are covered on their fused tip by the glans, which is part of the corpus spongiosus, containing the urethra and grown into position at an early embryonic stage. In the female fetus this growth does not occur and the anatomic description "glans clitoridis" is somewhat a misnomer. T h e area homologous to the glans penis is the central part of the vaginal vestibulum around the urethral opening. Levin@has recently studied whether this area is particularly stimulated during coital activity, and through stopped-frame video images of normal coitus been able to verify that the area is dragged into the vagina during penile intromission. On this basis, he has suggested that the area may act as the sensory input for the orgasmic reflex in women who achieve orgasm by penilelvaginal coitus alone. No specific studies on the sensitivity or reactivity of this particular area have been undertaken. Earlier investigations were centered around direct stimulation of the lito or is.^^^^^,^^ Thus, although we have increased our knowledge considerably during the last 25 years, there is still a great deal of information needed to make a complete picture. T h e same sentence that Regnier de Graafl wrote on May 12, 1668, in his preface to his treatise on male reproductive organs most probably can be used again in the future: "It is greatly to the interest of all mankind that what I have set forth in this little book should be widely known. Physical health is the greatest good of human life, and for its sake, this book describes many unheard-of things."'

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3. Klinge E, Sjostrand NO. Contraction and relaxation of the retractor penis muscle and the penile artery of the bull. Acta Physiol Scand 1974;93(420):1-109 4. Levin RJ. Functional anatomy of the female involved in sexual function. Clin Obstet Gynecol 1980;7:213-8 5. De Groat WC, Steers WD. Neuroanatomy and neurophysiology of' penile erection. In: Tanagho E, et al. Contemporary management of impotence and infertility. Baltimore: Williams & Wilkins, 1988:3-27 6. Sjostrand NO. Smooth muscles of vas deferens and other organs in the male reproductive tract. In: Biilbring E, Brading AF, Jones AW, Tomita T (eds): Smooth muscle: an assessment of current knowledge. London: Edward Arnold 198 1:367 7. Sjostrand NO, Klinge E. Principal mechanisms controlling penile retraction and protrusion in rabbits. Acta Physiol Scand 1979; 106: 199-207 8. Andersson PO, Bloom SR, Mellander S. Hemodynamics of pelvic nerve induced penile erection in the dog: possible mediation by vasoactive intestinal polypeptide. J Physiol (Lond) 1984;350:209-3 16 9. Wagner G, Uhrenholdt A. Blood flow measurement by the clearance method in the human corpus cavernosum in the flaccid and erect states. In: Zorgniotti AW, Rossi G (eds): Vasculogenic impotence. Proceedings of the First International Conference on Corpus Cavernosum Revascularization. Springfield, IL: Charles C Thomas, 1980:41-46 10. Wagner G, Green R. Impotence-physiological, psychological, surgical diagnosis and treatment. New York: Plenum Press, 1981 11. Wagner G, Willis EA, Bro-Rasmussen F, Nielsen MH. New theory on the mechanism of erection involving hitherto undescribed vessels. Lancet 1982; 1:416-8 12. Schmalbruch H, Wagner G. Vasoactive intestinal polypeptide (VIP)- and neuropeptide Y (NPY)-containing nerve fibres in the penile cavernous tissue of green monkeys (Cercopithecus aethiops). Cell Tissue Res 1989;256:529-36 13. Conti G. L'trection du ptnis humain et ses bases morphologico-vasculaires. Acta Anat 1952; l4:2 17-24 14. Newman HF, Northrup JD, Devil J. Mechanism of human penile erection. Invest Urol 1963; 1:350-4 15. Newman HF, Northrup JD. Mechanism of human penile erection: an overview. Urology 1981; l7:399-404 16. Benson GS. Penile erection: in a search of a neurotransmitter. World J Urol 1983; 1:209-14 17. Goldstein AMB, Mechan JP, Zakhary R, et al. New observations on microarchitecture of corpora cavernosa in man and possible relationship to mechanism of erection. Urology 1982;20:259-65 18. Lue TF, Zeineh SJ, Schmidt RA, Tanagho EA. Physiology of penile erection. World J Urol 1983; 1: 194-7 19. Wagner G. Electrical activity of grafted myometrium and its recording by radio-telemetry in unrestrained rabbits. J Physiol (Lond) 1975;244:353-60 20. Wagner G. Electrical activity of the corpus cavernosum: functional and pharmacological perspectives. In: Proceedings of the Third Biennial World Meeting on Impotence. Boston: lnternational Society of Impotence Research, 1988:7 21. Wagner G. Smooth muscle physiology in erection. Methods Clin Urodyn (spec vol) 1991;2-10 22. Wagner G, Gerstenberg T. Human in vivo studies of electrical activity of corpus cavernosum (EACC). J Urol 1988; 139:327A 23. Wagner G, Gerstenberg T, Levin RJ. Electrical activity of corpus cavernosum during flaccidity and erection of the human penis: a new diagnostic method? J Urol 1989; 142:723-7 24. Stief CG, Djamilian M, Schaebsday F et al. Single potential analysis of cavernous electrical activity-a possible diagnosis of autonomic impotence. World J Urol 1990;8:75-9

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nous injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology 1984; 35:79-84 Zorgniotti AW, Lefleur RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol 1985; 133:39-42 Brindley GS. Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis. Br J Pharmacol 1986;87:495-500 Brindley GS. A new treatment for priapism. Lancet 1984;2:220 Wagner G. Penile erection provoked by vibration and intracorporal injection. Nord Sexol 1985;3: 113-9 Wagner G, Kaplan HS. T h e new injection treatment for impotence. Medical and psychological aspects. New York: BrunnerIMazel, 1992 Jiinemann K-P, Alken P. Pharmacotherapy of erectile dysfunction. Int J Impotence Res 1989;1:71-93 Stief CG, Thon WF, Wetterauer U. Calcitonin-gene related peptide (CGRP): a possible neurotransmitter for human penile erection and its therapeutical application in impotent patients. In: Proceedings of the Symposium on Pharmacological Erection, Department of Urology, Herlev Hospital, University of Copenhagen, 1990 Gerstenberg TC, Metz P, Ottesen B, Fahrenkrug J. Intracavernous injection of vasoactive intestinal polypeptide (VIP) and phentolamine in the management of erectile failure. J Urol 1991; 145:404A Sjostrand NO. Les effecteurs de I'kmission du sperme. In: Soulairac A, Gautray J-P, Rousseau J-P, Cohen J (eds): S y s t h e Nerveux, ActivitC Sexuelle et Reproduction. Paris: Masson, 1976:263 De Groat WC. Spinal cord projections and neuropeptides in visceral afferent neurons. Brain Res 1986;67: 165 Owman C, Sjostrand NO. Short adrenergic neurons and catecholamine-containing cells in vas deferens and accessory male genital glands of different mammals. Z Zellforsch Mikrosk Anat 1965;66:300-6 Ventura WP, Freund M, Davis J, Pannuti MS. Influence of norepinephrine on the motility of the human vas deferens: a new hypothesis of sperm transport by the vas deferens. Fertil Steril 1973;24:68-72 Arver S, Sjostrand NO. Functions of adrenergic and cholinergic nerves in canine effectors of seminal emission. Acta Physiol Scand 1982;115:67-73 Hammarstrom M, Sjostrand NO. Intimacy of the neuroeffector junction and resistance to a-adrenoceptorblockade of the neurogenic contractile response in vasa deferentia from guinea pig and rat. Acta Physiol Scand 1984; 122:465-71 Hedlund H, Andersson K-E, Larsson B. Effect of drugs interacting with adrenoreceptors and muscarinic receptors in the epididymal and prostatic parts of the isolated human vas deferens. J Auton Pharmacol 1985; 5:261 Wagner G. Vaginal transudation. In: Beller FK, Schumacher JBF (eds): Biology of the fluids of the female genital tract. New York: Elsevier, 1979:25-37 Wagner G, Levin RJ. Effect of atropine and methylatropine on human vaginal blood flow, sexual arousal and climax. Acta Pharmacol Toxicol (Copenh) 1980;46: 32 1-5 Gillan P, Brindley GS. Vaginal and pelvic floor responses to sexual stimulation. Psychophysiology 1979;16:471-5 Levin RJ, Wagner G. Human vaginal motility during the menstrual cycle. J Physiol (Lond) 1983;342:24P Zacur HA, Genadry R, Rock JA, et al. Thyrotropinreleasing hormone-induced contraction of urethral and vaginal muscle. J Clin Endocrinol Metab 1985;61: 787-92 Levin RJ. VIP, vagina, clitoral and periurethral glansan update on human female genital arousal. Exp Clin Endocrinol 1991;98:61-9

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69. Fahrenkrug J. Co-existence and co-secretion of the structurally related peptides VIP and PHI. Scand J Clin Lab Invest 1987;47(suppl 186):43-50 70. Palle C, Bredkjaer HW, Ottesen B, Fahrenkrug J. Peptide histidine methionine (PHM) increases vaginal blood flow in normal women. Peptides 1990; 11:401-4 71. Kapian HS. T h e new sex therapy. New York: Brunnerl Mazel, 1974 72. Campbell B. Neurophysiology of the clitoris: In: Lowry TP, Lowry T S (eds): T h e clitoris. St. Louis: Warren H Green, 1976:35