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EVALUATION OF AUTONOMIC INNERVATION OF THE CLITORIS AND BULB
0022-5347/04/1725-1930/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 172, 1930 –1934, November 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000140760.79893.f1
Sexual Function/Infertility EVALUATION OF AUTONOMIC INNERVATION OF THE CLITORIS AND BULB UGUR YILMAZ, BRENDA G. KROMM
AND
CLAIRE C. YANG*
From the Department of Urology, University of Washington, Seattle, Washington
ABSTRACT
Purpose: Female sexual dysfunction is a common disorder but there are few objective measures of female genital function. We present a novel technique to record electrical activity of the female genital erectile tissue. Materials and Method: We placed concentric needle electrodes in the right clitoral crus and the bulb of 22 healthy women. Following spontaneous activity recording we stimulated the median nerve to activate the sympathetic nervous system. We simultaneously measured evoked activity in the clitoris and bulb, and hand sympathetic skin responses (SSRs). Results: Spontaneous electrical activity of the clitoris and bulb was present in 13 subjects. A total of 21 subjects had evoked activity in the bulb, while 18 had evoked activity in the clitoris. All subjects had hand SSRs. Evoked genital response latencies were similar to hand SSR latency (p ⬎0.05). Evoked electrical activity was recordable in the clitoris and bulb but it was more easily performed in the bulb. Conclusions: Evoked electrical activity is more consistently obtained than spontaneous activity. These tests represent possible objective measures of female genital autonomic innervation, which may have relevance to female sexual function. KEY WORDS: clitoris; genitalia, female; innervation; sympathetic nervous system
Female sexual dysfunction reportedly affects 43% of the women in the United States.1 Recently there has been a significant interest in the physiological mechanisms of female sexual function and dysfunction.2– 4 However, progress in clinical research has been slow, in part because of the lack of knowledge about female genital neurophysiology and the absence of universally accepted, objective measures of the female sexual response. One of the most common female sexual dysfunctions is arousal disorder, whereby women do not experience genital engorgement with sexual arousal.1 Based on anatomical studies of blood flow changes using magnetic resonance imaging the pelvic organs that become engorged during sexual arousal are the clitoris, labia minora and bulbs.5 The bulbs are oblong structures of erectile tissue located on either side of the female urethra. The vascular changes that occur in these organs with arousal are mediated by autonomic nerves. In men, autonomic innervation of the penis can be evaluated with neurophysiological techniques such as corpus cavernosum electromyography (CC-EMG) and evoked cavernous activity.6 –9 We modified these techniques and applied them to women with the intent of evaluating the autonomic innervation of female erectile tissue. The techniques are based on the rationale behind the sympathetic skin response (SSR) tests, whereby activation of the autonomic nervous system by an unexpected noxious stimulus (eg electrical stimulation of the median nerve) elicits sympathetically mediated sweat gland activity. We hypothesized that activation of the auto-
nomic nervous system should also be manifested in other autonomically innervated organs, such as erectile tissue. We performed preliminary studies of the clitoris and noted that electrical activity can be evoked and it is spontaneously recordable.10 The current study expands the earlier series and includes a technically easier method of recording activity from the erectile tissue of the bulbs. These measurements may be a method by which to determine the integrity of female genital innervation. MATERIALS AND METHOD
Anatomical dissection. In the female the clitoral body is palpable and needle insertion is readily performed. However, the bulbs are neither visible nor palpable on examination. Also, textbook descriptions of female genital anatomy are highly variable.11 To have a precise concentric needle insertion technique for the bulb we defined its 3-dimensional position by perineal dissections in 3 fixed female human cadavers. Dissection was initiated with a skin incision over the clitoral body extending on each side over the labia majora. The suspensory ligaments were dissected and the neurovascular bundle was defined beneath the overlying fatty tissue. The clitoral body and the 2 crura were carefully dissected beneath the ischiopubic rami. Labial dissection revealed the bulbs beneath subcutaneous fatty tissue. The bulbs were carefully dissected and their 3-dimensional relationship to the urethra and clitoris was defined with serial photographs. Electrophysiology. We recruited 22 healthy female subjects after the protocol was approved by the institutional review board at our hospital. Subjects were informed about the procedure and written consents were taken. They were asked
Accepted for publication June 25, 2004. Study received institutional review board approval. * Correspondence: Department of Urology, University of Washington, Box 356510, Seattle, Washington 98195-6510 (telephone: 206543-3640; FAX: 206-543-3272; e-mail: [email protected]). 1930
FEMALE GENITAL AUTONOMIC TESTING
to complete the Female Sexual Function Index (FSFI), a validated instrument of female sexual function.12 A full urological and neurological examination was done before the electrophysiological tests. Subjects were supine during the tests in a quiet room at ambient temperature (20C to 22C). One concentric, 20 mm, 0.4 mm diameter, gold plated needle electrode (Nicolet Biomedical, Madison, Wisconsin) was inserted into the right clitoral body from the cleft between the right labia minora and labia majora. A second concentric electrode was inserted into the right bulb 0.5 cm lateral from the edge of the urethral opening at an angle 10 to 20 degrees off of the axis of the urethra, as defined by the dissection. The electrode tips were 4 to 5 mm deep to the skin surface and fixed by taping the cables to the right leg. A ground electrode was placed on the lateral aspect of the right thigh. Following a quiet period of 5 minutes we recorded the spontaneous electrical activity of the clitoris and bulb for 10 minutes (Viking Select, Nicolet Biomedical). The filters were set at 0.2 to 100 Hz with a time base of 5 seconds per division. After spontaneous activity recording we stimulated the left median nerve at 7 to 8 mA for a duration of 0.5 milliseconds with a bipolar electrode. The stimuli were repeated 6 to 10 times at irregular intervals of more than 1 minute to avoid habituation (fading of the response). Evoked responses from the clitoris and bulb were recorded simultaneously at the same recording parameters as for spontaneous activity. We measured sympathetic skin potentials on the right hand at the same time as a control for evoked sympathetic discharge after median nerve stimulation. Two silver chloride disc electrodes were placed on the palmar and dorsal sides of the right hand as active and reference electrodes, respectively. The filters were the same as during spontaneous recording and the time base was set at 1 second per div. Response latencies were measured from the onset of the first waveform deflection and amplitudes were measured peak to peak. In the case of polyphasic waveforms amplitudes were measured between the peaks of the most robust waveform. The earliest latency and highest amplitude were used for statistical evaluation. To calculate the normal distribution of amplitudes and latencies the Kolmogorov-Smirnov test was used. The mean latencies and amplitudes of evoked bulbar and clitoral activities were compared with Student’s t test. RESULTS
Anatomical dissection. Anatomical dissection revealed the bulbs in close proximity to the clitoral crura and urethra (fig. 1). The bulbs joined the clitoral body distal to form the glans
1931
clitoris, as described by van Turnhout et al.13 The bulk of bulbar tissue was on either side of the urethra and displaced lateral and posterior toward their crural parts. The clitoral crura lying superior to the bulbs and urethra continued parallel to the ischiopubic rami bilaterally about 8 cm. FSFI scores. Female subjects were a mean ⫾ SD 27.4 ⫾ 5.7 years old (range 19 to 40) and the mean FSFI score was 29.7 ⫾ 3.5 (range 22 to 36). One subject did not complete the FSFI and those data were excluded from calculation of the mean FSFI score. The mean FSFI score and all individual FSFI scores were well within the normal ranges (30.5 ⫾ 5.3), as defined by Rosen et al,12 except in 1 subject who had a borderline normal total score of 22. Electrodiagnostic tests. Subjects tolerated testing well. There were complaints of discomfort with clitoral electrode placement. Bulbar electrode placement was not painful. There were no bleeding complications. Spontaneous Activity Recordings: Spontaneous activity comprised oscillating waveforms with highly variable amplitudes (fig. 2). Oscillations were not simultaneous within the clitoris and bulb. Furthermore, spontaneous activity was highly susceptible to motion artifact despite attempts to minimize subject movement. Since there was no stable oscillation pattern in the recorded activity, we did not attempt to make quantitative measurements of amplitudes or frequencies of the oscillations. Instead, we regarded them as present if they had oscillations with a recording sensitivity of 100 V and absent otherwise. A total of 13 subjects had spontaneous activity of the bulb and clitoris. Three subjects had only spontaneous bulbar activity without clitoral activity. One subject had only spontaneous clitoral activity without bulbar activity. Five subjects had no recordable spontaneous activity in either structure. Evoked Bulbar and Clitoral Activity: A total of 21 subjects had reproducible evoked bulbar activity. The remaining subject without evoked bulbar activity had evoked clitoral activity. A total of 18 subjects had evoked clitoral activity. Evoked bulbar and clitoral activity had normally distributed amplitude and latency measurements, as determined with the Kolmogorov-Smirnov test (p ⫽ 0.178 and 0.467 for the bulb, and p ⫽ 0.292 and 0.982 for the clitoris, respectively). Latency and amplitude measurements of clitoral and bulbar activity were statistically similar (p ⫽ 0.922 and 0.130, respectively, see table, fig. 3). Evoked clitoral and bulbar activity was liable to habituation, which could be overcome by increasing the interstimulus interval and avoiding regular stimulation at less than 1-minute intervals. Hand SSR: We obtained robust hand SSRs in all subjects. The Kolmogorov-Smirnov test confirmed the normal distri-
FIG. 1. A, photograph of dissected pelvis. Probe was placed into urethra and left labium was dissected to visualize clitoris and bulky bulbar tissue. B, drawing of photograph.
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FEMALE GENITAL AUTONOMIC TESTING DISCUSSION
FIG. 2. Spontaneous electrical activities of bulb and clitoris
Mean amplitude and latency of clitoral and bulbar evoked activity and hand SSRs
Amplitude (V): Bulb Clitoris Hand SSR Latency (msec): Bulb Clitoris Hand SSR
No. Subjects
Mean ⫾ SD
Min
Max
21 18 22
323.9 ⫾ 347.7 220.4 ⫾ 156.5 2,641.4 ⫾ 1,492.9
40 42 490
1,266 623 6,677
21 18 22
1,714.8 ⫾ 584.8 1,731.1 ⫾ 526.0 1,514.1 ⫾ 311.0
410 930 690
3,080 3,020 2,110
FIG. 3. Evoked clitoral and bulbar activities were recorded simultaneously with SSR. Two successive responses are shown to demonstrate reproducibility. L, latency. A, amplitude.
bution pattern of the latency and amplitude measurements of hand SSRs (p ⫽ 0.361 and 0.836, respectively). The amplitude of hand SSRs was higher than clitoral and bulbar evoked activities (each p ⬍0.001). Hand SSR latencies were not statistically different from the latencies of evoked clitoral and bulbar activity (p ⫽ 0.240 and 0.086, respectively, see table).
This study demonstrates spontaneous and evoked electrical activity in the clitoris and bulb. Evoked waveform latencies in the 2 structures were also temporally associated with those of hand SSRs, supporting our hypothesis that recorded genital activity is a reflection of sympathetic discharge. Evoked bulbar activity was more reproducible compared to evoked clitoral activity. Spontaneous activity was not as reliably obtained as evoked activity and it was highly variable in terms of the amplitude and frequency of oscillations. Evoked activity had a regular waveform, which allowed latency and amplitude measurements. The bulbs and clitoris consist of erectile tissue and their engorgement with sexual stimulation has been shown by magnetic resonance imaging.5, 14 Clitoral and bulbar engorgement, homologous to penile erection in the male, is a genital manifestation of female sexual arousal and it is mediated by autonomic fibers. A presumed etiology of genital arousal disorders is autonomic denervation of the female erectile tissue. In clinical practice there is a need for neurophysiological tests to assess the autonomic innervation of the female genitalia. To address this need we developed these tests based on the principles used in the assessment of autonomic innervation of the skin. Before the standardization of SSRs sudomotor activity was assessed by measuring changes in spontaneous electrical activity in a dermal area, called electrodermal activity.15, 16 Spontaneous activity recordings of genital erectile tissue are similarly measured. However, these measurements of spontaneous activity are difficult to quantitate. Sympathetic skin response is a measurement of sudomotor response to a triggering stimulus and it has become a method of evaluating the autonomic innervation of the skin.17, 18 Based on the same principle as SSRs other organ systems receiving sympathetic innervation could be tested with a startling stimulus, such as a sudden noise or an electrical impulse. The similar latency of SSRs, and the evoked activities in the clitoris and bulb seem to reflect a generalized orienting response to a startling stimulus mediated by the sympathetic nervous system (fig. 4). The difference between SSRs and genital evoked activities is that recording beneath the skin surface requires needle electrodes rather than surface electrodes. Since sympathetic and parasympathetic nerve pathways have common pathways after their exit from the pelvic plexus, assessing the sympathetic innervation with these tests would presumably reflect the status of general autonomic innervation of the genital tissue. Moreover, the sympathetic nervous system has been shown to have a role in the female sexual arousal response.2, 19 In our preliminary study we noted that it was possible to record evoked activities from the clitoris.10 However, the clitoris is small and manipulations of the needle electrode and its immobilization during the recording procedure are difficult. Furthermore, the technique is painful. Therefore, an alternative technique was necessary. Since the bulbs are also erectile tissue and should be innervated like the clitoris, we chose to investigate bulbar recordings. We found that electrode placement in the bulbs was technically easier and significantly less painful than clitoral electrode placement, making it a more attractive technique. The ease of bulbar electrode placement was due to its anatomical position as well as the mass of the tissue. We confirmed that the bulbs occupy a large space on either side of the urethra. Our findings were consistent with dissection performed by other groups.11, 13 The clitoris and bulbs share the same pattern of innervation and erectile response during sexual arousal and any neural deficit involving the efferent pathways to the clitoris should affect the bulbs in a similar fashion. In the current study we obtained similar evoked activity from the clitoris and bulb. The absence of simulta-
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anesthesia since the standard neuromuscular blockade does not block autonomic transmission. 3) Using pharmacological means to create even a sympathetic block would be difficult to titrate to the desired effect without significant sequelae. The origins of the genital responses will likely need to be demonstrated in an animal model. CONCLUSIONS
In the current study we describe electrodiagnostic techniques that may be useful for determining the integrity of female genital autonomic innervation based on the principles of dermal autonomic testing. Evoked bulbar activity is more robust and easier to perform than evoked clitoral activity. Spontaneous electrical activity recordings are highly variable, subject to artifacts and, thus, they are not as reliable as evoked recordings. The value of these tests for assessing female sexual dysfunction is the subject of ongoing investigations. REFERENCES
FIG. 4. Electrophysiological tests. Noxious stimulation of median nerve resulted in activation of autonomic nervous system. Resultant efferent response traveled down spinal cord, through pelvic plexus and through peripheral visceral efferent autonomic fibers innervating clitoris and bulb. Electrophysiological traces recorded in genital tissue are shown at bottom.
neity between the spontaneous activities of the 2 structures may have reflected differences in the sympathetic discharge delivered to each structure. The embryological homologues of the clitoris and bulbs in men are the corpora cavernosa and the corpus spongiosum surrounding the urethra.13, 20 In men evoked cavernous activity in the penis can be recorded after a startling stimulus, such as a sudden noise or electrical stimulus of a somatosensory nerve.6, 7 Spontaneous electromyographic activity within the corpus cavernosa of the penis is also recordable, known as CC-EMG.8, 9 There are several controversies related to male genital smooth muscle electrophysiological tests, primarily regarding CC-EMG, which may be pertinent to female genital electrophysiological tests. One of the controversies is that corpus cavernosum electromyography is a motion artifact recording. When considering the frequency band pass filters used for smooth muscle recording in the male and female genitalia, the high pass filter is quite low (0.2 Hz) (as used for electrodermal activity and SSR recordings), allowing the detection of low frequency signals such as smooth muscle motion. However, based on the current study we cannot claim to know the origins of the recorded potentials. We are not presuming to have measured actual electrical activity of smooth muscle or electromyographic activity in terms of standard skeletal muscle electromyography. Therefore, we chose to use the term electrical activity rather than electromyography. Ideally we would be able to identify the origins of the response by ablating it through an autonomic blockade or by a selective sympathetic blockade. The feasibility of demonstrating either of these blocks in the clinical setting is limited for several reasons. 1) Localized neural blockade is not possible because the autonomic neuroanatomy of the female genitalia has not been defined. 2) Systemic autonomic blockade is not clinically feasible even in the operating room with
1. Laumann, E. O., Paik, A. and Rosen, R. C.: Sexual dysfunction in the United States: prevalence and predictors. JAMA, 281: 537, 1999 2. Meston, C. M. and Gorzalka, B. B.: Differential effects of sympathetic activation on sexual arousal in sexually dysfunctional and functional women. J Abnorm Psychol, 105: 582, 1996 3. Berman, J. R., Berman, L. and Goldstein, I.: Female sexual dysfunction: incidence, pathophysiology, evaluation, and treatment options. Urology, 54: 385, 1999 4. Rosen, R. C. and McKenna, K. E.: PDE-5 inhibition and sexual response: pharmacological mechanisms and clinical outcomes. Annu Rev Sex Res, 13: 36, 2002 5. Suh, D. D., Yang, C. C., Cao, Y., Heiman, J. R., Garland, P. A. and Maravilla, K. R.: MRI of female genital and pelvic organs during sexual arousal: initial experience. Unpublished data ¨ 6. Yilmaz, U., Soylu, A., Ozcan, C., Kutlu, R. and Gu¨nes, A.: Evoked cavernous activity. J Urol, 167: 188, 2002 7. Yarnitsky, D., Sprecher, E., Barilan, Y. and Vardi, Y.: Corpus cavernosum electromyogram: spontaneous and evoked electrical activities. J Urol, 153: 653, 1995 8. Stief, C. G., Kellner, B., Hartung, C., Hauck, E., Schlote, N., Truss, M. et al: Computer-assisted evaluation of the smoothmuscle electromyogram of the corpora cavernosa by fast Fourier transformation. Eur Urol, 31: 329, 1997 9. Sasso, F., Stief, C. G., Gulino, G., Alcini, E., Junemann, K. P., Gerstenberg, T. et al: Progress in corpus cavernosum electromyography (CC-EMG)-third international workshop on corpus cavernosum electromyography (CC-EMG). Int J Impot Res, 9: 43, 1997 10. Yilmaz, U., Soylu, A., Ozcan, C. and Caliskan, O.: Clitoral electromyography. J Urol, 167: 616, 2002 11. O’Connell, H. E., Hutson, J. M., Anderson, C. and Plenter, R. J.: Anatomical relationship between urethra and clitoris. J Urol, 159: 1892, 1998 12. Rosen, R., Brown, C., Heiman, J., Leiblum, S., Meston, C., Shabsigh, R. et al: The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther, 26: 191, 2000 13. van Turnhout, A. A., Hage, J. J. and van Diest, P. J.: The female corpus spongiosum revisited. Acta Obstet Gynecol Scand, 74: 767, 1995 14. Maravilla, K. R., Heiman, J. R., Garland, P. A., Cao, Y., Carter, W. O., Peterson, B. T. et al: Dynamic MR imaging of the sexual arousal response in women. J Sex Marital Ther, suppl., 29: 71, 2003 15. Lader, M. H. and Wing, L.: Habituation of the psycho-galvanic reflex in patients with anxiety states and in normal subjects. J Neurol Neurosurg Psychiatry, 27: 210, 1964 16. Ionescu-Tirgoviste, C. and Pruna, S.: Quantitative noninvasive electrophysiological evaluation of the activity of the cutaneous division of the sympathetic nervous system. Arch Int Physiol Biochim, 98: 111, 1990 17. Shahani, B. T., Halperin, J. J., Boulu, P. and Cohen, J.: Sympathetic skin response—a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J Neurol Neuro-
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surg Psychiatry, 47: 536, 1984 18. Claus, D. and Schondorf, R.: Sympathetic skin response. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl, 52: 277, 1999 19. Meston, C. M. and Gorzalka, B. B.: The effects of sympathetic activation on physiological and subjective sexual arousal in women. Behav Res Ther, 33: 651, 1995 20. Baskin, L. S., Erol, A., Li, Y. W., Liu, W. H., Kurzrock, E. and Cunha, G. R.: Anatomical studies of the human clitoris. J Urol, 162: 1015, 1999 EDITORIAL COMMENTS These authors present ground breaking work in the understudied field of female sexual dysfunction. In this report they describe a novel technique to measure quantitatively the electrical activity of the female genitalia. Needle electrodes were reproducibly placed in the bulb and clitoris, measuring electrical activity in response to sympathetic stimulation of the median nerve. The authors evaluated 22 healthy women and noted that evoked electrical activity was consistently obtained in response to sympathetic stimulation. This is a first step to developing a clinical test to measure quantitatively normal female sexual function. Laurence Baskin Pediatric Urology University of California-San Francisco Children’s Hospital San Francisco, California These authors present a highly novel study of female sexual neurophysiology. In a series of 22 subjects evoked potentials and spontaneous electrical activity in the clitoral body and clitoral bulbs were measured. These data were contrasted with synchronous activity in the skin of the hand resulting from stimulation of the median nerve (SSRs). These techniques have been used in the neurophysiological evaluation of male erectile difficulties. Subjects were evaluated with a standardized and validated questionnaire (FSFI) and found to have
normal sexual function. Electrode placement was guided by a series of clitoral dissections. Of the 22 subjects 21 had reproducible evoked bulb activity, while the remaining patient having activity in the clitoral body. Spontaneous activity of the clitoral body and bulb was present in 13 subjects, in the bulbs only in 3, in the clitoral body only in 1 and it was absent in the 2 structures in 5. The exact place of this testing in the neuropathic patient or patient with sexual dysfunction remains to be seen. Bulbar testing was found to be pain-free and it is unclear how well tolerated was placement of electrodes in the clitoral corpora. Measurement of such tolerability with a visual analog scale may be useful in future research when comparing methods of testing female sexual function. Dissection reveals that the clitoral bulbs have no tunica, as distinct from the clitoral corpora which, like the penile tunica, is a tough and thick layer surrounded by branches of the dorsal clitoral nerve. The bulbs by comparison are relatively large (larger than the conjoined male bulb), providing an easier target for electrode placement than the corpora, which are less than 1 cm in diameter and relatively inaccessible. The clitoral bulbs and body contain erectile tissue. We recently reported the histology of the bulbs1 but their physiology has not been investigated until now. Further research would be required to determine the origin of these presumptive autonomic responses, the major clitoral neurovascular supply being the pudendal in origin with a contribution from the cavernous nerves. This preliminary study leads the way for a test of pelvic neural integrity and female sexual function. Helen E. O’Connell Department of Surgery Royal Melbourne Hospital Melbourne, Victoria Australia 1. O’Connell, H. E., Anderson, C. R., Flenter, R. J. and Hutson, J. M.: The clitoris: a unified structure— histology of the clitoral glans, body, crura and bulbs. Unpublished data
Vol. 172, 1930 –1934, November 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000140760.79893.f1
Sexual Function/Infertility EVALUATION OF AUTONOMIC INNERVATION OF THE CLITORIS AND BULB UGUR YILMAZ, BRENDA G. KROMM
AND
CLAIRE C. YANG*
From the Department of Urology, University of Washington, Seattle, Washington
ABSTRACT
Purpose: Female sexual dysfunction is a common disorder but there are few objective measures of female genital function. We present a novel technique to record electrical activity of the female genital erectile tissue. Materials and Method: We placed concentric needle electrodes in the right clitoral crus and the bulb of 22 healthy women. Following spontaneous activity recording we stimulated the median nerve to activate the sympathetic nervous system. We simultaneously measured evoked activity in the clitoris and bulb, and hand sympathetic skin responses (SSRs). Results: Spontaneous electrical activity of the clitoris and bulb was present in 13 subjects. A total of 21 subjects had evoked activity in the bulb, while 18 had evoked activity in the clitoris. All subjects had hand SSRs. Evoked genital response latencies were similar to hand SSR latency (p ⬎0.05). Evoked electrical activity was recordable in the clitoris and bulb but it was more easily performed in the bulb. Conclusions: Evoked electrical activity is more consistently obtained than spontaneous activity. These tests represent possible objective measures of female genital autonomic innervation, which may have relevance to female sexual function. KEY WORDS: clitoris; genitalia, female; innervation; sympathetic nervous system
Female sexual dysfunction reportedly affects 43% of the women in the United States.1 Recently there has been a significant interest in the physiological mechanisms of female sexual function and dysfunction.2– 4 However, progress in clinical research has been slow, in part because of the lack of knowledge about female genital neurophysiology and the absence of universally accepted, objective measures of the female sexual response. One of the most common female sexual dysfunctions is arousal disorder, whereby women do not experience genital engorgement with sexual arousal.1 Based on anatomical studies of blood flow changes using magnetic resonance imaging the pelvic organs that become engorged during sexual arousal are the clitoris, labia minora and bulbs.5 The bulbs are oblong structures of erectile tissue located on either side of the female urethra. The vascular changes that occur in these organs with arousal are mediated by autonomic nerves. In men, autonomic innervation of the penis can be evaluated with neurophysiological techniques such as corpus cavernosum electromyography (CC-EMG) and evoked cavernous activity.6 –9 We modified these techniques and applied them to women with the intent of evaluating the autonomic innervation of female erectile tissue. The techniques are based on the rationale behind the sympathetic skin response (SSR) tests, whereby activation of the autonomic nervous system by an unexpected noxious stimulus (eg electrical stimulation of the median nerve) elicits sympathetically mediated sweat gland activity. We hypothesized that activation of the auto-
nomic nervous system should also be manifested in other autonomically innervated organs, such as erectile tissue. We performed preliminary studies of the clitoris and noted that electrical activity can be evoked and it is spontaneously recordable.10 The current study expands the earlier series and includes a technically easier method of recording activity from the erectile tissue of the bulbs. These measurements may be a method by which to determine the integrity of female genital innervation. MATERIALS AND METHOD
Anatomical dissection. In the female the clitoral body is palpable and needle insertion is readily performed. However, the bulbs are neither visible nor palpable on examination. Also, textbook descriptions of female genital anatomy are highly variable.11 To have a precise concentric needle insertion technique for the bulb we defined its 3-dimensional position by perineal dissections in 3 fixed female human cadavers. Dissection was initiated with a skin incision over the clitoral body extending on each side over the labia majora. The suspensory ligaments were dissected and the neurovascular bundle was defined beneath the overlying fatty tissue. The clitoral body and the 2 crura were carefully dissected beneath the ischiopubic rami. Labial dissection revealed the bulbs beneath subcutaneous fatty tissue. The bulbs were carefully dissected and their 3-dimensional relationship to the urethra and clitoris was defined with serial photographs. Electrophysiology. We recruited 22 healthy female subjects after the protocol was approved by the institutional review board at our hospital. Subjects were informed about the procedure and written consents were taken. They were asked
Accepted for publication June 25, 2004. Study received institutional review board approval. * Correspondence: Department of Urology, University of Washington, Box 356510, Seattle, Washington 98195-6510 (telephone: 206543-3640; FAX: 206-543-3272; e-mail: [email protected]). 1930
FEMALE GENITAL AUTONOMIC TESTING
to complete the Female Sexual Function Index (FSFI), a validated instrument of female sexual function.12 A full urological and neurological examination was done before the electrophysiological tests. Subjects were supine during the tests in a quiet room at ambient temperature (20C to 22C). One concentric, 20 mm, 0.4 mm diameter, gold plated needle electrode (Nicolet Biomedical, Madison, Wisconsin) was inserted into the right clitoral body from the cleft between the right labia minora and labia majora. A second concentric electrode was inserted into the right bulb 0.5 cm lateral from the edge of the urethral opening at an angle 10 to 20 degrees off of the axis of the urethra, as defined by the dissection. The electrode tips were 4 to 5 mm deep to the skin surface and fixed by taping the cables to the right leg. A ground electrode was placed on the lateral aspect of the right thigh. Following a quiet period of 5 minutes we recorded the spontaneous electrical activity of the clitoris and bulb for 10 minutes (Viking Select, Nicolet Biomedical). The filters were set at 0.2 to 100 Hz with a time base of 5 seconds per division. After spontaneous activity recording we stimulated the left median nerve at 7 to 8 mA for a duration of 0.5 milliseconds with a bipolar electrode. The stimuli were repeated 6 to 10 times at irregular intervals of more than 1 minute to avoid habituation (fading of the response). Evoked responses from the clitoris and bulb were recorded simultaneously at the same recording parameters as for spontaneous activity. We measured sympathetic skin potentials on the right hand at the same time as a control for evoked sympathetic discharge after median nerve stimulation. Two silver chloride disc electrodes were placed on the palmar and dorsal sides of the right hand as active and reference electrodes, respectively. The filters were the same as during spontaneous recording and the time base was set at 1 second per div. Response latencies were measured from the onset of the first waveform deflection and amplitudes were measured peak to peak. In the case of polyphasic waveforms amplitudes were measured between the peaks of the most robust waveform. The earliest latency and highest amplitude were used for statistical evaluation. To calculate the normal distribution of amplitudes and latencies the Kolmogorov-Smirnov test was used. The mean latencies and amplitudes of evoked bulbar and clitoral activities were compared with Student’s t test. RESULTS
Anatomical dissection. Anatomical dissection revealed the bulbs in close proximity to the clitoral crura and urethra (fig. 1). The bulbs joined the clitoral body distal to form the glans
1931
clitoris, as described by van Turnhout et al.13 The bulk of bulbar tissue was on either side of the urethra and displaced lateral and posterior toward their crural parts. The clitoral crura lying superior to the bulbs and urethra continued parallel to the ischiopubic rami bilaterally about 8 cm. FSFI scores. Female subjects were a mean ⫾ SD 27.4 ⫾ 5.7 years old (range 19 to 40) and the mean FSFI score was 29.7 ⫾ 3.5 (range 22 to 36). One subject did not complete the FSFI and those data were excluded from calculation of the mean FSFI score. The mean FSFI score and all individual FSFI scores were well within the normal ranges (30.5 ⫾ 5.3), as defined by Rosen et al,12 except in 1 subject who had a borderline normal total score of 22. Electrodiagnostic tests. Subjects tolerated testing well. There were complaints of discomfort with clitoral electrode placement. Bulbar electrode placement was not painful. There were no bleeding complications. Spontaneous Activity Recordings: Spontaneous activity comprised oscillating waveforms with highly variable amplitudes (fig. 2). Oscillations were not simultaneous within the clitoris and bulb. Furthermore, spontaneous activity was highly susceptible to motion artifact despite attempts to minimize subject movement. Since there was no stable oscillation pattern in the recorded activity, we did not attempt to make quantitative measurements of amplitudes or frequencies of the oscillations. Instead, we regarded them as present if they had oscillations with a recording sensitivity of 100 V and absent otherwise. A total of 13 subjects had spontaneous activity of the bulb and clitoris. Three subjects had only spontaneous bulbar activity without clitoral activity. One subject had only spontaneous clitoral activity without bulbar activity. Five subjects had no recordable spontaneous activity in either structure. Evoked Bulbar and Clitoral Activity: A total of 21 subjects had reproducible evoked bulbar activity. The remaining subject without evoked bulbar activity had evoked clitoral activity. A total of 18 subjects had evoked clitoral activity. Evoked bulbar and clitoral activity had normally distributed amplitude and latency measurements, as determined with the Kolmogorov-Smirnov test (p ⫽ 0.178 and 0.467 for the bulb, and p ⫽ 0.292 and 0.982 for the clitoris, respectively). Latency and amplitude measurements of clitoral and bulbar activity were statistically similar (p ⫽ 0.922 and 0.130, respectively, see table, fig. 3). Evoked clitoral and bulbar activity was liable to habituation, which could be overcome by increasing the interstimulus interval and avoiding regular stimulation at less than 1-minute intervals. Hand SSR: We obtained robust hand SSRs in all subjects. The Kolmogorov-Smirnov test confirmed the normal distri-
FIG. 1. A, photograph of dissected pelvis. Probe was placed into urethra and left labium was dissected to visualize clitoris and bulky bulbar tissue. B, drawing of photograph.
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FIG. 2. Spontaneous electrical activities of bulb and clitoris
Mean amplitude and latency of clitoral and bulbar evoked activity and hand SSRs
Amplitude (V): Bulb Clitoris Hand SSR Latency (msec): Bulb Clitoris Hand SSR
No. Subjects
Mean ⫾ SD
Min
Max
21 18 22
323.9 ⫾ 347.7 220.4 ⫾ 156.5 2,641.4 ⫾ 1,492.9
40 42 490
1,266 623 6,677
21 18 22
1,714.8 ⫾ 584.8 1,731.1 ⫾ 526.0 1,514.1 ⫾ 311.0
410 930 690
3,080 3,020 2,110
FIG. 3. Evoked clitoral and bulbar activities were recorded simultaneously with SSR. Two successive responses are shown to demonstrate reproducibility. L, latency. A, amplitude.
bution pattern of the latency and amplitude measurements of hand SSRs (p ⫽ 0.361 and 0.836, respectively). The amplitude of hand SSRs was higher than clitoral and bulbar evoked activities (each p ⬍0.001). Hand SSR latencies were not statistically different from the latencies of evoked clitoral and bulbar activity (p ⫽ 0.240 and 0.086, respectively, see table).
This study demonstrates spontaneous and evoked electrical activity in the clitoris and bulb. Evoked waveform latencies in the 2 structures were also temporally associated with those of hand SSRs, supporting our hypothesis that recorded genital activity is a reflection of sympathetic discharge. Evoked bulbar activity was more reproducible compared to evoked clitoral activity. Spontaneous activity was not as reliably obtained as evoked activity and it was highly variable in terms of the amplitude and frequency of oscillations. Evoked activity had a regular waveform, which allowed latency and amplitude measurements. The bulbs and clitoris consist of erectile tissue and their engorgement with sexual stimulation has been shown by magnetic resonance imaging.5, 14 Clitoral and bulbar engorgement, homologous to penile erection in the male, is a genital manifestation of female sexual arousal and it is mediated by autonomic fibers. A presumed etiology of genital arousal disorders is autonomic denervation of the female erectile tissue. In clinical practice there is a need for neurophysiological tests to assess the autonomic innervation of the female genitalia. To address this need we developed these tests based on the principles used in the assessment of autonomic innervation of the skin. Before the standardization of SSRs sudomotor activity was assessed by measuring changes in spontaneous electrical activity in a dermal area, called electrodermal activity.15, 16 Spontaneous activity recordings of genital erectile tissue are similarly measured. However, these measurements of spontaneous activity are difficult to quantitate. Sympathetic skin response is a measurement of sudomotor response to a triggering stimulus and it has become a method of evaluating the autonomic innervation of the skin.17, 18 Based on the same principle as SSRs other organ systems receiving sympathetic innervation could be tested with a startling stimulus, such as a sudden noise or an electrical impulse. The similar latency of SSRs, and the evoked activities in the clitoris and bulb seem to reflect a generalized orienting response to a startling stimulus mediated by the sympathetic nervous system (fig. 4). The difference between SSRs and genital evoked activities is that recording beneath the skin surface requires needle electrodes rather than surface electrodes. Since sympathetic and parasympathetic nerve pathways have common pathways after their exit from the pelvic plexus, assessing the sympathetic innervation with these tests would presumably reflect the status of general autonomic innervation of the genital tissue. Moreover, the sympathetic nervous system has been shown to have a role in the female sexual arousal response.2, 19 In our preliminary study we noted that it was possible to record evoked activities from the clitoris.10 However, the clitoris is small and manipulations of the needle electrode and its immobilization during the recording procedure are difficult. Furthermore, the technique is painful. Therefore, an alternative technique was necessary. Since the bulbs are also erectile tissue and should be innervated like the clitoris, we chose to investigate bulbar recordings. We found that electrode placement in the bulbs was technically easier and significantly less painful than clitoral electrode placement, making it a more attractive technique. The ease of bulbar electrode placement was due to its anatomical position as well as the mass of the tissue. We confirmed that the bulbs occupy a large space on either side of the urethra. Our findings were consistent with dissection performed by other groups.11, 13 The clitoris and bulbs share the same pattern of innervation and erectile response during sexual arousal and any neural deficit involving the efferent pathways to the clitoris should affect the bulbs in a similar fashion. In the current study we obtained similar evoked activity from the clitoris and bulb. The absence of simulta-
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anesthesia since the standard neuromuscular blockade does not block autonomic transmission. 3) Using pharmacological means to create even a sympathetic block would be difficult to titrate to the desired effect without significant sequelae. The origins of the genital responses will likely need to be demonstrated in an animal model. CONCLUSIONS
In the current study we describe electrodiagnostic techniques that may be useful for determining the integrity of female genital autonomic innervation based on the principles of dermal autonomic testing. Evoked bulbar activity is more robust and easier to perform than evoked clitoral activity. Spontaneous electrical activity recordings are highly variable, subject to artifacts and, thus, they are not as reliable as evoked recordings. The value of these tests for assessing female sexual dysfunction is the subject of ongoing investigations. REFERENCES
FIG. 4. Electrophysiological tests. Noxious stimulation of median nerve resulted in activation of autonomic nervous system. Resultant efferent response traveled down spinal cord, through pelvic plexus and through peripheral visceral efferent autonomic fibers innervating clitoris and bulb. Electrophysiological traces recorded in genital tissue are shown at bottom.
neity between the spontaneous activities of the 2 structures may have reflected differences in the sympathetic discharge delivered to each structure. The embryological homologues of the clitoris and bulbs in men are the corpora cavernosa and the corpus spongiosum surrounding the urethra.13, 20 In men evoked cavernous activity in the penis can be recorded after a startling stimulus, such as a sudden noise or electrical stimulus of a somatosensory nerve.6, 7 Spontaneous electromyographic activity within the corpus cavernosa of the penis is also recordable, known as CC-EMG.8, 9 There are several controversies related to male genital smooth muscle electrophysiological tests, primarily regarding CC-EMG, which may be pertinent to female genital electrophysiological tests. One of the controversies is that corpus cavernosum electromyography is a motion artifact recording. When considering the frequency band pass filters used for smooth muscle recording in the male and female genitalia, the high pass filter is quite low (0.2 Hz) (as used for electrodermal activity and SSR recordings), allowing the detection of low frequency signals such as smooth muscle motion. However, based on the current study we cannot claim to know the origins of the recorded potentials. We are not presuming to have measured actual electrical activity of smooth muscle or electromyographic activity in terms of standard skeletal muscle electromyography. Therefore, we chose to use the term electrical activity rather than electromyography. Ideally we would be able to identify the origins of the response by ablating it through an autonomic blockade or by a selective sympathetic blockade. The feasibility of demonstrating either of these blocks in the clinical setting is limited for several reasons. 1) Localized neural blockade is not possible because the autonomic neuroanatomy of the female genitalia has not been defined. 2) Systemic autonomic blockade is not clinically feasible even in the operating room with
1. Laumann, E. O., Paik, A. and Rosen, R. C.: Sexual dysfunction in the United States: prevalence and predictors. JAMA, 281: 537, 1999 2. Meston, C. M. and Gorzalka, B. B.: Differential effects of sympathetic activation on sexual arousal in sexually dysfunctional and functional women. J Abnorm Psychol, 105: 582, 1996 3. Berman, J. R., Berman, L. and Goldstein, I.: Female sexual dysfunction: incidence, pathophysiology, evaluation, and treatment options. Urology, 54: 385, 1999 4. Rosen, R. C. and McKenna, K. E.: PDE-5 inhibition and sexual response: pharmacological mechanisms and clinical outcomes. Annu Rev Sex Res, 13: 36, 2002 5. Suh, D. D., Yang, C. C., Cao, Y., Heiman, J. R., Garland, P. A. and Maravilla, K. R.: MRI of female genital and pelvic organs during sexual arousal: initial experience. Unpublished data ¨ 6. Yilmaz, U., Soylu, A., Ozcan, C., Kutlu, R. and Gu¨nes, A.: Evoked cavernous activity. J Urol, 167: 188, 2002 7. Yarnitsky, D., Sprecher, E., Barilan, Y. and Vardi, Y.: Corpus cavernosum electromyogram: spontaneous and evoked electrical activities. J Urol, 153: 653, 1995 8. Stief, C. G., Kellner, B., Hartung, C., Hauck, E., Schlote, N., Truss, M. et al: Computer-assisted evaluation of the smoothmuscle electromyogram of the corpora cavernosa by fast Fourier transformation. Eur Urol, 31: 329, 1997 9. Sasso, F., Stief, C. G., Gulino, G., Alcini, E., Junemann, K. P., Gerstenberg, T. et al: Progress in corpus cavernosum electromyography (CC-EMG)-third international workshop on corpus cavernosum electromyography (CC-EMG). Int J Impot Res, 9: 43, 1997 10. Yilmaz, U., Soylu, A., Ozcan, C. and Caliskan, O.: Clitoral electromyography. J Urol, 167: 616, 2002 11. O’Connell, H. E., Hutson, J. M., Anderson, C. and Plenter, R. J.: Anatomical relationship between urethra and clitoris. J Urol, 159: 1892, 1998 12. Rosen, R., Brown, C., Heiman, J., Leiblum, S., Meston, C., Shabsigh, R. et al: The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther, 26: 191, 2000 13. van Turnhout, A. A., Hage, J. J. and van Diest, P. J.: The female corpus spongiosum revisited. Acta Obstet Gynecol Scand, 74: 767, 1995 14. Maravilla, K. R., Heiman, J. R., Garland, P. A., Cao, Y., Carter, W. O., Peterson, B. T. et al: Dynamic MR imaging of the sexual arousal response in women. J Sex Marital Ther, suppl., 29: 71, 2003 15. Lader, M. H. and Wing, L.: Habituation of the psycho-galvanic reflex in patients with anxiety states and in normal subjects. J Neurol Neurosurg Psychiatry, 27: 210, 1964 16. Ionescu-Tirgoviste, C. and Pruna, S.: Quantitative noninvasive electrophysiological evaluation of the activity of the cutaneous division of the sympathetic nervous system. Arch Int Physiol Biochim, 98: 111, 1990 17. Shahani, B. T., Halperin, J. J., Boulu, P. and Cohen, J.: Sympathetic skin response—a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J Neurol Neuro-
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surg Psychiatry, 47: 536, 1984 18. Claus, D. and Schondorf, R.: Sympathetic skin response. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl, 52: 277, 1999 19. Meston, C. M. and Gorzalka, B. B.: The effects of sympathetic activation on physiological and subjective sexual arousal in women. Behav Res Ther, 33: 651, 1995 20. Baskin, L. S., Erol, A., Li, Y. W., Liu, W. H., Kurzrock, E. and Cunha, G. R.: Anatomical studies of the human clitoris. J Urol, 162: 1015, 1999 EDITORIAL COMMENTS These authors present ground breaking work in the understudied field of female sexual dysfunction. In this report they describe a novel technique to measure quantitatively the electrical activity of the female genitalia. Needle electrodes were reproducibly placed in the bulb and clitoris, measuring electrical activity in response to sympathetic stimulation of the median nerve. The authors evaluated 22 healthy women and noted that evoked electrical activity was consistently obtained in response to sympathetic stimulation. This is a first step to developing a clinical test to measure quantitatively normal female sexual function. Laurence Baskin Pediatric Urology University of California-San Francisco Children’s Hospital San Francisco, California These authors present a highly novel study of female sexual neurophysiology. In a series of 22 subjects evoked potentials and spontaneous electrical activity in the clitoral body and clitoral bulbs were measured. These data were contrasted with synchronous activity in the skin of the hand resulting from stimulation of the median nerve (SSRs). These techniques have been used in the neurophysiological evaluation of male erectile difficulties. Subjects were evaluated with a standardized and validated questionnaire (FSFI) and found to have
normal sexual function. Electrode placement was guided by a series of clitoral dissections. Of the 22 subjects 21 had reproducible evoked bulb activity, while the remaining patient having activity in the clitoral body. Spontaneous activity of the clitoral body and bulb was present in 13 subjects, in the bulbs only in 3, in the clitoral body only in 1 and it was absent in the 2 structures in 5. The exact place of this testing in the neuropathic patient or patient with sexual dysfunction remains to be seen. Bulbar testing was found to be pain-free and it is unclear how well tolerated was placement of electrodes in the clitoral corpora. Measurement of such tolerability with a visual analog scale may be useful in future research when comparing methods of testing female sexual function. Dissection reveals that the clitoral bulbs have no tunica, as distinct from the clitoral corpora which, like the penile tunica, is a tough and thick layer surrounded by branches of the dorsal clitoral nerve. The bulbs by comparison are relatively large (larger than the conjoined male bulb), providing an easier target for electrode placement than the corpora, which are less than 1 cm in diameter and relatively inaccessible. The clitoral bulbs and body contain erectile tissue. We recently reported the histology of the bulbs1 but their physiology has not been investigated until now. Further research would be required to determine the origin of these presumptive autonomic responses, the major clitoral neurovascular supply being the pudendal in origin with a contribution from the cavernous nerves. This preliminary study leads the way for a test of pelvic neural integrity and female sexual function. Helen E. O’Connell Department of Surgery Royal Melbourne Hospital Melbourne, Victoria Australia 1. O’Connell, H. E., Anderson, C. R., Flenter, R. J. and Hutson, J. M.: The clitoris: a unified structure— histology of the clitoral glans, body, crura and bulbs. Unpublished data