Review Article

Clinical Autonomic Research 2001, 11:279-283

The effect of various spinal lesions on female sexual response has recently been investigated in detail. Studies of women with neurologic disabilities and studies of animal models have provided substantial information regarding the spinal control of sexual responses. In this report, the authors explore findings regarding the neurologic pathways underlying the spinal control of sexual arousal and orgasm. Information available about the effects of multiple sclerosis and v~riou~ cerebral disorders on female sexual function will also be reviewed, with special attention to areas where further research is needed. Lastly, the current status and techniques available to improve the sexual functioning of women with neurologic disabilities affecting the central nervous system will be reviewed.

Neurogenic female sexual dysfunction: a review

Key words:female sexual response, spinal cord injury, multiple sclerosis, brain injury, sexuality.

Marca L. Sipski, M.D.,1'2 and Anousheh Behnegar, M . D . 3 1Department of Veteran Affairs, ~Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida; 3Mt. Sinai School of Medicine, New York, New York, USA

Address correspondence and reprint requests to Marca L. Sipski, M.D., Miami VA Medical Center, 1201 N.W. 16th Street (128), Miami, FL 33125, U.S.A. Tel: 305-324-3174; Fax: 305-324-3161

ReceivedAugust 14, 2001; accepted September 3, 2001

Sexual dysfunction is a significant problem that can affect the quality of life of 20% to 50% of women [1-3]. It is more prevalent in American women (43%) than men (31%) [3]. A person's sexual functioning is the result of a combination of biological, psychologic and interpersonal determinants such as aging, relationship status, medical concerns, and emotional state. A change in any of these areas could therefore lead to sexual dysfunction. Until recent years, very little attention was paid to understanding the nuances of female sexual function. However, the neurologic basis of female sexual response has recently been investigated in humans. Studies of women's genital, subjective, and autonomic responses to various combinations of erotic stimulation have been conducted. Moreover, studies have targeted women with specific neurologic disabilities in order to determine the source of spinal mediation of sexual response. This information is important because, unless the natural history of various neurologic lesions on sexual function is known, the sexual potential of women with varying patterns of neurologic injuries cannot be assessed. Coupling this fact with the myriad of issues contributing to a person's sexuality makes treatment of sexual dysfunction in a woman with neurologic disability next to impossible. The goal of this paper is to review the impact of various neurologic lesions on female sexuality, response, and function. A basic premise will be, that similarly located neurologic lesions should result in similar changes in sexual response. Therefore, we will group disorders based upon their location in the neuraxis.

F e m a l e sexual response following s p i n a l cord dysfunction The vast majority of literature that pertains to women with neurologic disorders is related to spinal cord injuries (SCIs). The frequency of sexual activity is generally known to decrease after SCI [4-6]. Moreover, sexual satisfaction has also been shown to decrease [6]. Although questionnaire studies have been used extensively to document the effects of various levels and degrees of SCI on male sexual response [7], this methodolo D, did not prove a viable means to study female sexual response, probably because women have internal genitalia as opposed to men [6]. In order to determine the effects of specific patterns and degrees of SCIs on female sexual response, an accurate means of determining the presence of vaginal vasocongestion must be used. Vaginal p h o t o p l e t h y s m o g r a p h y [8J--specifically, the measurement of vaginal pulse amplit u d e - i s considered the preferred method [9] for the assessment of vaginal blood flow. This technique was recently used to demonstrate the inability of women with complete SCIs a t T 6 and above [10] to achieve psychogenically based genital arousal, despite evidence of subjective sexual arousal. Further work in women with incomplete injuries a t T 6 and above [11] provided preliminary support for the hypothesis that the sympathetic nervous system is the source of psychogenically mediated genital response in women. Analysis of women with SCIs and upper motor neuron neurologic dysfunction affecting the sacral spinal segments also disclosed preservation o f the ability to elicit genital 0959-9851 9 2001 Lippincott Williams & Wilkins 279

Sipski and Behnegar vasocongestion manually without further increases in subjective sexual arousal [10,11]. This is believed to be a demonstration of reflex genital vasocongestion. Further laboratory-based studies [12] of women with levels of SCIs ranging from C 4 to L 5 and with both complete and incomplete injuries have demonstrated differences in genital responsiveness to audio-visual stimulation. These differences (in the ability to achieve psychogenic genital arousal) are based upon the extent of the ability to perceive a combination of pinprick and light touch sensation in the T I l - L 2 dermatomes. Regardless of the level of the injury, significant differences in response were observed, depending on the degree of sensory preservation at T l l - L 2. Those women with the greatest ability to perceive surface stimulation were shown to have the greatest ability for psychogenic genital vasocongestion, whereas those with little and no ability to perceive sensation in this area had relatively less potential for psychogenic genital vasocongestion. In contrast, no differences in genital responsiveness occurred when women with SCIs were classified based upon their ability to perceive sensation in the sacral ($2-S 5) or thoracic (T6-T9) dermatomes. This finding is supportive of the sympathetic nervous system being in control of psychogenic genital arousal due to the sympathetic cell bodies location in the intermediolateral cell columns at T 1l-L2. Here the intermediolateral cell column and sympathetic cell bodies in lamina VII are in close proximity to the cell bodies of neurons whose axons traverse the spinothalamic tracts in lamina V. The axons of neurons destined to enter the spinothalamic tracts cross through lamina VI, VII and X to ascend the contralateral side of the spinal cord [13]. Therefore, cell body damage causing a loss of pain and touch sensation is likely to occur in close proximity to the sympathetic cell bodies responsible for psychogenic genital arousal. A decrease in preservation o f o n e function is therefore associated with a decrease in the other. Recent research in sexually functional and dysfunctional noninjured females has also supported the belief that sympathetic stimulation will increase female genital blood flow. Exercise, the use of anxiety-provoking videos, and ephedrine [14-16] have been used as a means of increasing sympathetic tone during sexual stimulation. Moreover, these research findings have consistently demonstrated that increased activity of the sympathetic nervous system resulted in increased genital and subjective sexual arousal. These findings dispute the hypothesis that sexual arousal in women is mediated by parasympathetic fibers [17]. Cell bodies of the parasympathetic nervous system lie in the $2-S 4 segments of the spinal cord in the sacral parasympathetic nucleus. If the parasympathetic nervous system were responsible for psychogenic genital vasocongestion, greater damage at the $2-S 4 level of the spinal cord should be associated with a greater decrease in psychogenic genital vasocongestion, similar to the findings concerning T 1l-L2. This is not the case; therefore, this research suggests that in human females psychogenic genital vasocongestion is primarily a function of the sympathetic nervous system. 280

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Basic science studies in rats in both sexes have disclosed sympathetic and parasympathetic preganglionic neurons going out to the cavernous nerve [18]. In female rats the cavernous nerve is known to provide a vasodilatory innervation to the clitoris [17]. The function of the parasympathetic fibers in rats has been determined to include clitoral engorgement, vaginal vasocongestion, and lubrication; however, the function of the sympathetic fibers has only been postulated as being "mainly inhibitory to genital arousal" [17]. Perhaps the reason for this discrepancy with humans is one of the limitations in performing basic science studies pertaining to sexuality: that animals cannot effectively communicate their degree of sexual arousal or sensory experience as humans can. Therefore, although parasympathetic stimulation in the rat may result in genital vasocongestion, this may actually be a pathway for reflexive genital vasocongestion in the rat that still needs to be elucidated. Moreover, the potential for the sympathetic fibers in the rat to be both excitatory and inhibitory may not yet have been determined. The ability of human females with complete and incomplete SCIs to achieve orgasm has also been documented [5,6,19]. The occurrence of orgasm in women with complete SCIs at T 6 and above was noted as support for the foundation of orgasm to be a pelvic reflex response [20-23]. Additionally, it was proposed that the sensations associated with orgasm are at least in part based upon afferent autonomic innervation, which remains even in the presence of complete SCI [19]. Alternatively, the ability of only three women with complete SCIs below T 6 to achieve orgasm through directed cervical stimulation was the human basis for a hypothesis that the vagus nerve innervates the cervix and is therefore responsible for the sensory experience of orgasm in women [24]. This belief was also based upon findings in the rat, that the vagus nerves provide a sensory pathway from the reproductive tract directly to the medulla oblongata of the brain, bypassing the spinal cord [25]. However, we observed the orgasmic experiences of 37 women [12] and found that the descriptions of orgasm of women with varying levels of complete and incomplete SCIs are indistinguishable from those of noninjured women. Based upon these findings, we hypothesize that the sensory experience of orgasm is possibly on an autonomic basis and may occur without cerebral transmission of impulses, similar to menstrual sensations or the urge to void or defecate in SCI patients with high-level complete injuries. Research also demonstrates a probable inability of women with complete lower motor neuron dysfunction affecting $2-$5 to achieve orgasm via direct genital stimulation [12]. Findings suggest that the neurologic potential for orgasm should remain with all other levels and degrees of spinal cord dysfunction. It must be noted that other factors, such as medications, depression, and physical and/or emotional problems with their partners probably contribute to orgasmic dysfunction in many women with SCIs. The autonomic responses accompanying orgasm in women with SCIs and those observed in noninjured women were quite

Central nervous system dysfunction and female sexual function similar. Physiologically, mild increases in heart rate and blood pressure were observed in both groups [12]. Latency to orgasm was, however, significantly greater in women with SCIs. Orgasmic difficulties in some women may occur, therefore, because they give up and do not allow sufficient stimulation to occur to reach orgasm. Based upon recent research, it can be hypothesized that orgasm occurs as a reflex function that can be augmented or inhibited by supraspinal innervation in noninjured individuals. This would be similar to bladder and bowel function, which rely on similar neurologic input and occur reflexively in infants and persons with complete SCIs but are under cerebral control during the majority of life. This hypothesis is also consistent with animal studies, whereby genital stimulation of anesthetized acutely spinalized rats results in a response resembling orgasm in human with rhythmic contractions of the striated perineal muscles and vaginal and uterine contractions [26]. This is also not a completely unique finding, in that visceral sensations are preserved, even in the presence of complete SCIs [27]. Women with SCIs are able to perceive menstrual cramps [5] and labor pain [28]. Moreover, persons with long-standing SCIs have been shown to experience sensations of rectal distension [29] and the urge to void. Finally, neurogenic pain is commonly observed in persons with complete SCIs [30].

Multiple sclerosis Multiple sclerosis (MS) potentially impacts the spinal cord and the brain and, as might be expected, the impact of MS on sexual functioning is variable [31]. Research has shown that as many as 72% of women with MS have sexual dysfunction [32]. Moreover, complaints may be related to physiologic and psychologic issues. A decrease in libido has been documented in 28% [33] to 60% [34] of women with MS. With regard to sexual response, 36% of a group of 47 women with advanced MS reported difficulties with lubrication [34]. In the same group, 38% reported decreased orgasmic capacity and 28% were anorgasmic since their disease. Anorgasmia was also noted in 37%, and decreased orgasm in another 37% of a group of 149 women with MS [35]. Unfortunately, neither of these reports provided detailed information about the subjects' neurologic conditions so that conclusions could be made about the potential direct neurologic effects of their MS on their sexual potential. Other reports, however, have begun to map out specific neurologic lesions associated with MS and how sexual response is affected. Concerning spinal effects, a recent electrodiagnostic study of 14 women with MS showed statistically significant abnormalities or absence of one or both pudendal somatosensory evoked potentials in the women with orgasmic difficulties [36]. Hulter and Lundberg [34] also correlated pelvic floor weakness, bladder and bowel dysfunction, and changes in lubrication and orgasmic capacity and noted that these results emphasize how the same segments of the autonomic nervous system are responsible

for bladder, bowel, and sexual function. These findings of sexual difficulties associated with lesions in the sacral segment are in concordance with findings in women with SCIs that an intact sacral reflex arc is necessary to achieve orgasm [12]. Additionally, with regard to other neurologic findings, another study [33] examining 32 females and 9 males with MS noted that anorgasmia correlated with brain stem and pyramidal abnormalities and the total area of plaques observed on the brain via magnetic resonance imaging.

Female sexual response following brain dysfunction In contrast to our knowledge base in SCI, much of our knowledge about the impact of various brain lesions on sexual function is based upon animal studies. Sexual function is known to be under descending control from brain stem sites, but until recently the details of this control were unknown [26]. The nucleus paragigantocellularis receives genital sensory information in both males and females [37,38], and projects directly to pelvic neurons and interneurons in the lumbosacral spinal cord [39]. Lesions of the nucleus paragigantocellularis have been shown to suppress tonic inhibition of the climax-like response of the rat [39]. Moreover, the nucleus stains positively for serotonin [40] and may be the source for the high incidence of sexual dysfunction associated with serotonin-specific reuptake inhibitors [26]. The periaqueductal gray has also been shown to have connections with brain stem sites and hypothalamic sites involved in sexual function [41]. The hypothalamus is also a crucial structure in the elaboration of the human sexual response; however, its roles have not yet been precisely defined. The medial preoptic area has been hypothesized to be involved with mate selection, whereas the paraventricular nucleus is considered to be involved in the control of sexual responses [26]. Minimal information is available regarding the impact of traumatic brain injuries (TBI) in humans on female sexual function. One group studied 13 women and 39 men with TBIs [42] and found that those subjects with frontal lobe injuries had better sexual functioning than those with injuries to other parts of the brain. In another study 65 men and 27 women, status post-TBI, were interviewed at an average of 9 years after injury [43]. Decreases in frequency of intercourse, ability to achieve orgasm, and sexual interest were noted after injury. In the largest study (and the only with a nondisabled control group) [44], 193 men and 129 women with TBI were queried about their sexual functioning. Women with TBIs reported greater difficulties in sexual arousal, pain with sex, masturbation, and vaginal lubrication than nondisabled women. Additionally, an endocrine disorder and level of depression combined were the most sensitive predictors of sexual difficulties in women with TBIs. The impact of hypothalamic disorders on sexual function has been considered [45]; however, only one report was noted. The effects of hypothalamic-pituitary dysfunction were assessed in 48 women (median age 42 y). Menstrual Clinical Autonomic Research 2001, Vol 11 No 5

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Sipski and Behnegar irregularity was usually the first symptom, occurring between ages 16 to 35. Ninety-four percent of subjects noted previous or current significant sexual problems. Decreased libido was reported by 79.2%. Lubrication was diminished in 64.6%; orgasmic dysfunction was reported by 68.7%. Normal menses, youth, and intrasellar tumor growth were associated with more normal sexual desire and response than prolactin or testosterone concentrations. Serum testosterone concentrations correlated significantly only with masturbation. Cerebral vascular accidents (CVAs) may be a better model of brain disorder because the injuries are usually better localized than with TBIs. However, persons with CVAs are often older and have concomitant medical problems that can affect sexual function. Therefore, only the most well controlled studies are noted. Prospectively [46], 38 men and 12 women (aged 32-65), free from other neurological dysfunction, severe aphasia, and psychiatric or medical disorders were queried about the impact of their CVAs on sexual function. Satisfaction with their sexual activity decreased from 90% being moderately or very satisfied with their sexual lives before CVA to 42% after CVA (p <0.001). Retrospectively, of 117 men and 75 women [47], 89% noted satisfaction with their sexual life before their CVA as compared with 49% reporting moderate or complete dissatisfaction after CVA. Unfortunately, results were not separated according to gender. With regard to sexual arousal, 10 women followed prospectively [46] after CVA were queried about lubrication; 6 noted difficulties. In the same group, an additional 20% of subjects became anorgasmic subsequent to their CVAs. Retrospectively, of 75 women [47], 47% had normal lubrication before CVA whereas only 24% reported normal lubrication after CVA; 34% reported diminished lubrication after CVA as compared with 29% before; 12% reported no lubrication after CVA as compared with 4% before. In the same group, only 16% reported normal orgasms after stroke compared with 48% before. Overall, our knowledge of the impact 'of brain disorders on female sexuality remains limited. There is a lack of controlled studies and in those that exist very little detail is provided about the subject's neurologic dysfunction. Laboratory-based research in humans is also nonexistent. Because of this, the origins of cognitive sexual arousal in women remain undefined, as does the expected natural history of varying cerebral disorders and lesions on female sexuality and response. This is especially important as female sexual dysfunction becomes more well defined [1], because personal distress is considered a significant prerequisite to diagnose sexual dysfunction. Yet one of the anticipated effects of brain injury may be to limit interest in sexual activity so much that the woman is not personally distressed by her decreased function [48]. Future research in women with well-defined patterns of brain dysfunction should clarify the precise extent of their lesions and the impact of location and degree of injury on sexual desire and response. Imaging techniques with computed tomography scanning and magnetic resonance imaging should be used to clarify the degree 282

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of women's neurologic dysfunction and attempt to translate animal findings into humans. Once the expected natural history of these disorders is defined, future work can explore remediation of specific sexual dysfunctions.

Rehabilitation and treatment of female sexual dysfunction Treatment of any neurologic-related sexual dysfunction begins with education of the patient about the impact of his or her neurologic disability on sexual functioning. The more informed the woman is about the expected impact of a disorder on her sexual response, the greater the chance she will have to regain sexual function. The more exact the information available about the impact of various neurologic disorders on female sexual functioning, therefore, the more likely that she will have optimal sexual functioning. Limited attention has been paid to treating female sexual dysfunctions, especially when one considers the vast information pertaining to treatment of erectile dysfunction. A recent study {49] looked at the use of positive feedback to increase sexual arousal and noted that significant increases in subjective arousal occurred with the use of false-positive feedback. Moreover, increased genital responsiveness was noted in SCI subjects with the capacity for psychogenic genital responsiveness. Although techniques have been developed to facilitate orgasm in noninjured women with anorgasmia, no real treatment programs have been developed to tackle orgasmic dysfunction in women with neurologic disability. With regard to medical management, new treatments that have recently been developed for male erectile dysfunction may be useful for improving women's sexual function. Phosphodiesterase type 5 and nitric oxide-cyclic guanine monophosphate activity have been found in human clitoral tissue [50]. Therefore, it appears that the drug sildenafil, originally used to remediate erectile dysfunction, may have effects on women's genital function. Because sildenafll was shown to have superior efficacy in men with SCIs as compared with other etiologies of erectile dysfunction [51,52], a laboratory-based, double-blind, crossover design study was conducted in 19 women with all levels of SCI [53]. A significant increase in subjective sexual arousal with drug as compared with placebo (p <0.01) was noted. Overall, the drug was well tolerated without evidence of significant adverse events. Based on the recent progress in studying women with SCIs, the future looks bright for expanding our knowledge of sexual function in women with other neurologic disabilities. Future research should focus on further delineation of the relation between discrete patterns of neurologic dysfunction and their impact on specific aspects of sexual response. Correlation of findings between animal and human models should be continued. Pilot studies of the effects ofsildenafil, ephedrine, and other new drugs under development for erectile dysfunction on sexual response in women with SCIs and other neurologic injuries should be considered. Moreover, a systematic approach using controlled research tech-

Central nervous system dysfunction and female sexual function niques should be used to determine which therapies would be useful for testing in clinical trials. N o w that questions about women's sexuality are finally beginning to be asked, we must continue to delve into this area of research that is ever so important to the quality of life.

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