Kluver-Bucy syndrome

Chronic neurologic disease can have a tremendous impact on a woman's health and self-image. One area of her life that can be affected by neurologic disease is sexual functioning. Lesions in the brain, spinal cord, and peripheral nerves subserving sexual functions can diminish a woman's libido and ability to become sexually aroused, as well as alter the experience of orgasm. Muscular weakness or spasticity may hinder movement and mobility during sexual activity. Psychological and social factors resulting from dealing with a chronic, irreversible neurologic disease may cause further sexual dysfunction.

The following is a review of female sexual function in the context of common neurologic diseases that can affect the sexually active woman, with an emphasis on the neurologic elements of sexual dysfunction. The intent of this article is to stimulate interest in the neurologic aspects of female sexual function, particularly with regard to neuroanatomy and neuropathology. Diseases that are well defined neuroanatomically and neuropathologically will be used to illustrate the influence of particular areas of the nervous system on sexual function (listed in descending order from the brain): epilepsy/cerebral cortex, Parkinson's disease/basal ganglia, multiple sclerosis/brain and spinal cord, spinal cord injury/spinal cord, and diabetes/peripheral nerves. Other neurologic diseases with less discretely defined pathology will be discussed briefly.

Treatment options are limited and typically do not involve reversal of the neurologic problem. The emphasis here will be on medical therapies; psychosocial therapies are beyond the scope of this review. Neurologic aspects of fertility and reproduction will not be discussed. Although in the past they were considered alongside sexuality, they are now regarded as separate physiologic entities. Finally, a discussion on possible directions for neuroscience-based research in female human sexual function is included.

NEUROANATOMY AND NEUROPHYSIOLOGY OF THE FEMALE SEXUAL RESPONSE

To appreciate the effects of neurologic disease on the female sexual response, some understanding of the pertinent neuroanatomy and neurophysiology is necessary. Unfortunately, little is known about these areas. There have been many extrapolations made from the anatomy and physiology of the male sexual response, though such conclusions may not be valid. Elucidation of the pertinent components of the nervous system is critical in the study of the neurophysiology of the female sexual response, and should be an area of active research.

The innervation of the female genital tract is mediated through the somatic and the autonomic nervous systems (see Figure 1) (Anderson and Genadry, 1996). Somatic innervation is primarily conducted through branches of the pudendal nerve, of which the first two branches are involved with sexual function. The pudendal nerve is derived from sacral spinal segments 2 through 4, and travels laterally through the pelvis. It begins branching after exiting the pudendal canal on the inner aspect of the inferior pubic ramus. The first branch, the dorsal nerve of the clitoris, is a purely sensory nerve, without any known motor functions. It carries somatosensory impulses from the clitoris. The second branch of the pudendal nerve, the perineal nerve, provides sensory branches to the perineum, labia majora, labia minora, and distal third of the vagina. It also provides motor innervation to the striated pelvic floor muscles (Takahashi & Sato, 1985), which contract during sexual arousal and orgasm (Gillan & Brindley, 1979).

[Figure 1 ILLUSTRATION OMITTED]

Autonomic innervation of the female genitalia is comprised of fibers from both the sympathetic and parasympathetic nervous systems (Anderson, 1996). It is believed that the anatomic arrangements of these nerves resemble that of the male. The sympathetic fibers are derived from the lower thoracic and upper lumbar spinal segments (T10-L2), and the parasympathetic fibers are derived from S2-4. These fibers then coalesce in the pelvis and redistribute to the genital endorgans (uterus, cervix, proximal 2/3 of the vagina). Sensory afferents are mediated through the visceral afferent fibers derived from the same spinal segments. Although this arrangement is generally accepted to be true, careful dissection studies in humans have not been well documented.

Female sexual responsivity is a result of sensory input through the peripheral nerves of the somatic and autonomic nervous system, as well as through the cranial nerves and psychogenic stimulation. How and where the afferent information is processed within the spinal cord and brain is unknown. There are several areas within the brain that appear to be related to sexual responsivity, including the frontal lobe (Dua & MacLean, 1964) and anterior hypothalamus (Edwards & Einhorn, 1986), but none of these has been definitively identified as crucial portions of female (or male) human sexuality. Kluver-Bucy syndrome, resulting from bilateral temporal lobe lesions, has hypersexuality as one of its manifestations (Lilly, Cummings, Benson, & Frankel, 1983), suggesting that the temporal lobes are important in regulation of sexual arousal.

The resultant genital motor responses to sexual stimulation include pelvic vasocongestion and vaginal lubrication, mediated by vasoactive neurotransmitters such as vasoactive intestinal peptide, neuropeptide Y, substance P, calcitonin gene-related peptide, and helospectin and others (Hauser-Kronberger et al., 1999); vaginal lengthening and tonic contraction; labial size increase; uterine elevation; and clitoral retraction (Masters & Johnson, 1966). With orgasm, the motor responses include pelvic musculature and uterine contractions (Masters & Johnson, 1966). Pelvic striated muscle contractions are subserved by the (somatic) perineal nerve (Takahashi & Sato, 1985), and autonomic fibers send efferent impulses to effect the other visceral motor responses. More research is needed to clarify the neuroanatomic aspects of the human female genitalia.

FEMALE SEXUAL DYSFUNCTION IN NEUROLOGIC DISEASE

Epilepsy

Epilepsy is a very common neurologic disorder resulting from abnormal recurrent electrical discharges of the cerebral cortex. Epilepsy can manifest at any age, with a wide range of etiologies such as cerebral trauma, infection, or ischemia, though most cases are idiopathic. There are two major categories of seizure disorders: (a) primary, generalized seizures, which occur in both cortical hemispheres without local onset, and include generalized tonic/clonic seizures and absence seizures; and (b) partial seizures, which begin at a focal point within the brain but may progress to a generalized seizure. Treatment for epilepsy is primarily through the use of antiepileptic medications, which act to depress cortical electrical activity.

Sexual dysfunction in epilepsy has been clinically documented for some time, although a recent report from Jensen et al. (1990) concluded that epilepsy did not necessarily increase the risk of sexual dysfunction in males or females. When sexual dysfunction is noted, it generally arises after the onset of seizures, and may be more common in partial than in primary generalized epilepsies. In another study, women with epilepsy reported fewer sexual experiences than similarly aged women, and expressed less arousal and more anxiety in response to imagined sexual activities (Morrell, Sperling, Stecker, & Dichter, 1994). Temporal lobe epilepsy commonly results in hyposexual behavior, most commonly failure to orgasm, but can also result in increased desire for sexual activity (Blumer, 1970). Sexual dysfunction in this population may be due to disruption of cortical regions mediating hormonal regulation (Herzog, Seibel, Schomer, Vaitukaitis, & Geschwind, 1986) or sexual behavior, such as the limbic cortex and the frontal lobe (although these areas have only been defined in animal models) (Dua & MacLean, 1964; Edwards & Einhom, 1986). In addition, antiepileptic medications may contribute to sexual dysfunction by directly affecting hormonal changes (Mattson & Cramer, 1985), although this is debatable (Jensen et al., 1990).

Morell et al. (1994) reported that women with epilepsy registered a smaller increase in genital blood flow as measured by photoplethysmography during visual sexual stimulation as compared to control women. In addition, diminution in genital vasocongestion in response to sexually arousing stimuli was demonstrated in some women with temporal lobe epilepsy without an accompanying diminution in self-perceived sexual arousal (Morrell et al., 1994). This discrepancy between perceived functionality and measured diminution in genital blood flow may be explained by the fact that these women may have been diagnosed with their disease prior to becoming sexually active, or at a younger age, and thus were not able to compare their responses to a premorbid state. Alternatively, this particular subgroup of women may have found ways in which to minimize or bypass their dysfunction (e.g., topical lubricant use for vaginal dryness) and thus may not consider themselves dysfunctional.

Changes in sexual behavior, though uncommon, have been seen in patients with epilepsy, including hypersexuality, pansexuality, erotomania, sexual paranoia, exhibitionism, and fetishism (Lundberg, 1980).

Parkinson's Disease/Parkinson's Syndrome

Parkinsonism is a term used to describe a set of symptoms associated with motor abnormalities due to lesions of the basal ganglia. These symptoms include motor rigidity, uncoordination, akinesia/hypokinesia, alterations of posture, and involuntary movements. The pathophysiologic process is related to a relative deficiency of dopamine in the basal ganglia nuclei, which is the primary neurotransmitter for this portion of the brain. In the United States, Parkinsonism affects approximately one percent of adults over 50 years of age (Adams & Victor, 1993). Recently more attention has been drawn to the development of this disease in the fourth decade of life and earlier (approximately 5 to 10 percent of cases; see Golbe, 1991). Treatment is aimed at dopamine replacement within the basal ganglia, using a dopaminergic precursor combined with a decarboxylase inhibitor (Sinemet) or with dopamine agonists.

Very few studies have examined the incidence of sexual dysfunction in Parkinson's disease (PD). One report of a study including 14 women stated that 70% of the women had decreased sexual interest, 67% had difficulty with arousal, 75% had decreased frequency of orgasm since the onset of parkinsonism, and 38% were anorgasmic (Koller et al., 1990). While some of these symptoms can be attributed to changes brought on by senescence, the symptoms of motor disability and depression, common findings that are associated with PD (Adams & Victor, 1993), can also contribute to the dysfunction. Wermuth and Stenager (1995) reported that 7 of 10 young women with PD (ages 36-56) had decreased libido, and 8 of 10 had a decrease in sexual activity since the onset of the disease (Wermuth & Stenager, 1995). Although 7 women were menopausal, there was a temporal relationship of sexual dysfunction to the number of years of PD treatment. The authors postulated the decrease in libido might be related to the dopaminergic transmitter system.

Multiple Sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system, beginning most often in late adolescence and early adult life and expressed by discrete and recurrent attacks of spinal cord, brainstem, cerebellar, optic nerve, and cerebral dysfunction. The neurologic symptoms are a result of destruction of myelin, though axons may also be affected. In certain areas of the northern United States, the prevalence is as high as 69 to 122 per 100,000 population, with females affected more than males (approximately 1.5-3:1; see Poser, 1998; Sadiq & Miller, 1995). Neurologic symptoms of MS are highly variable, and there are several forms of the disease, based on its progression and the presence or absence of relapses. Typically, patients become gradually more handicapped over the course of many years. Medical treatment is aimed at slowing the progression of the disease and symptom management.

The occurrence of sexual dysfunction in women with MS has been documented in several studies, with the incidence ranging from 50 to 70% (Barak et al., 1996; Hulter & Lundberg, 1995; Lilius, Voltonen, & Wikstrom, 1976; Valleroy & Kraft, 1984). The most common complaints were of fatigue, loss of libido, and decreased genital sensation (Barak et al., 1996; Lundberg, 1980; Valleroy & Kraft, 1984). Sexual dysfunction correlates highly with the presence of bladder and/or bowel symptoms, supporting the hypothesis that the dysfunction is a direct result of the neurologic process, since the innervation of the lower genitourinary tract and the anorectal complex are derived from the same spinal segments. Other factors, such as hormonal imbalance, would not explain the occurrence of disturbances in bowel and bladder function in concert with sexual dysfunction. Female endocrine studies have not been performed, and the role of endocrine dysfunction in female sexuality has not been defined in women with MS. Duration of the disease does not appear to be correlated with the presence of sexual dysfunction (Mattson, Petrie, Srivastava, & McDermott, 1995), since progression of the disease varies with the subtype of MS. Preliminary electrodiagnostic studies suggest that sexual symptoms may be attributable to a lesion in the conus medullaris (Taylor, Bradley, Bhatia, Glick, & Haldeman, 1984), or regions higher in the neuraxis (Yang, unpublished data).

Spinal Cord Injury and Related Disorders

Trauma is the most common cause of spinal cord disease. In civilian life, this can be a result of motor vehicle accidents, recreational injuries (e.g., diving, boating), and construction injuries. There are approximately 8,000 to 10,000 persons in the U.S. with spinal cord injuries, with a 4 to 1 male predominance (Levine, Eismont, Garfin, & Zigler, 1998; Meyer, Cybulski, Rusin, & Haak, 1995). The majority of affected persons are injured in the young adult years. Other spinal cord disorders can result from tumors, infection, and vertebral bony disease.

Spinal cord injury (SCI) is typically classified by the level of injury: cervical (C), thoracic (T), lumbar (L), or sacral (S) spinal level. In addition, the type of injury can be classified as complete, wherein somatic sensation (e.g., from the skin) is completely absent, no voluntary muscle activity is present below the level of spinal injury, and spinal reflexes are abolished at the level of injury; and incomplete, where there may be variable degrees of sensory, motor, and reflex activity below the level of injury (Levine et al., 1998). Quadriplegia (or tetraplegia) refers to the state where a person is impaired in all four extremities (usually a cervical spinal injury), or paraplegia, where the impairment is limited to the lower extremities (thoracic or lumbar injury). Further classification of spinal injury can be made using detailed assessments (American Spinal Injury Association [ASIA] Neurological Standards Committee, 1996); however, this is not likely to add to the assessment of sexual function since level of injury is not necessarily related to the degree of sexual impairment (see below).

Because genital innervation is mediated primarily through the most caudal portions of the spinal cord, spinal cord injury at any point along the spinal column may affect sexual responsiveness in women. Overall sexual satisfaction and frequency of sexual activity is decreased in most women after SCI, but SCI did not necessarily preclude enjoyment with sexual activity (Dellfitting, Salisbury, Daview, & Mayclin, 1978; Sipski & Alexander, 1993).

Clinical patterns are present based on a person's level of injury and its severity. For example, a person with a complete injury at T1 will be unable to control her bowel or bladder evacuation and does not have somatic sensation or movement below the level of injury, but is able use her hands and arms. Early studies seemed to indicate a similar pattern with regard to sexual function and spinal injury level as well. Berard (1989) stated that there is absence of lubrication, either reflex or psychogenic, when the injury is between T10 and T12, but psychogenic lubrication is possible below an injury at T12 and reflex lubrication at levels above T9. Complete injuries typically resulted in sexual inarousability of somatically innervated body parts below the level of injury, whereas incomplete injuries resulted in some sensation and arousability. Interestingly, within the same study, three complete quadriplegics reported arousability following breast stimulation, and two reported clitoral arousability (Berard, 1989).

More recent studies demonstrated that the ability to orgasm does not appear to depend on the level or completeness of injury. Sipski and Alexander (1993) reported that 11 of 25 women with all levels of spinal injury were able to climax. However, only 2 of these women reported that the sensation of climax was the same as pre-injury; the others reported decreased or different sensations. Women with otherwise complete lesions still have some sense of deep vaginal penetration; perhaps the visceral afferent fibers of the cervix, upper vagina, and/or uterus are mediating these sensations through tracts bypassing the spinal cord (Komisaruk, Gerdes, & Whipple, 1997). Comarr and Vigue (1978) postulated that SCI women can reach orgasm by stimulation of other erogenous areas (presumably above the level of injury), and that women incorporate fantasy more readily than men into their sexual activity to achieve sexual stimulation and climax.

There are many other factors associated with SCI that may affect a woman's sexual functioning. Altered body shape and image, bladder and bowel incontinence, muscle spasticity, and immobility can all contribute to a decrease in desire or ability to be sexually active. Autonomic dysreflexia (AD) is due to noxious stimuli below the level of injury and is a common sequela of persons injured at T6 or higher (Young & Woolsey, 1995). AD results in severe and potentially malignant hypertension, sweating above the level of injury, and headache. The hypertension is often so severe that emergent measures are needed to avoid a cerebrovascular accident. Sipski and Alexander (1993) reported that 6 of 25 SCI women in their series reported AD with intercourse, and 4 were uncertain if they had AD with sexual activity.

Diabetes Mellitus

Diabetes is an endocrine disorder resulting from inadequate release of insulin, which causes abnormal carbohydrate metabolism commonly defined by hyperglycemia. It is not a primary neurologic disorder, but one of the most common sequela is diabetic polyneuropathy, which affects approximately 50% of type I and type II diabetics (Dyck et al., 1993). The neuropathic process is believed to be due to a combination of vascular changes resulting in neuronal ischemia and biochemical changes (Stevens, Feldman, & Greene, 1995).

Because sexual dysfunction was found to be very common in diabetic men (Kolodny, Kahn, Goldstein, & Barnett, 1974), it was assumed that diabetic women would also suffer from sexual dysfunction. In the 1970s, the first studies were published that examined sexual function in women with diabetes. Kolodny (1971) interviewed 125 diabetic and 100 nondiabetic women to determine the incidence of sexual dysfunction in these two groups. The most notable difference was a 35% incidence of anorgasmia in the diabetic group compared with 6% in the nondiabetic group. Sexual dysfunction correlated strongly with duration of diabetes, but there was little association with age, insulin dose, or the presence of other diabetic sequelae (Kolodny, 1971). Ellenberg (1977) evaluated 54 diabetic women with neuropathy and 46 diabetic women without neuropathy, aged 24-73, and found no difference in libido or orgasmic capacity between the two groups. There was no comparison to nondiabetic women. Notable was the fact that approximately 80% of both groups retained libido and orgasmic function.

More recent studies revealed more specific information regarding diabetes and female sexual functioning. Sexual responsiveness in 82 insulin-dependent women was assessed, and these women were found to be no less orgasmic than nondiabetic controls, even in the presence of autonomic neuropathy (Tyrer et al., 1983). Fifty insulin-dependent women were followed for 6 years, and the frequency of sexual dysfunction was similar at the start and end of the observation period (Jensen, 1986). Six of 14 women who were sexually dysfunctional at the start of the study recovered normal function, some of them in the face of neuropathic findings. Schriener-Engel, Schiavi, Vietorisz, and Smith (1987) reported that type I diabetes had little or no effect on women, while type II diabetes had a negative impact on libido, orgasmic capacity, and sexual satisfaction. Thirty African American women with diabetes were compared to 33 nondiabetic women, and the diabetic women had significantly lower levels of sexual desire. Both groups were similar in reports of sexual arousal, orgasm, and sexual satisfaction, and sexual function was not found to be related to duration of disease and glycosylated hemoglobin levels (Watts, 1994). Women's acceptance of illness was a strong predictor of sexual function, and thus sexual function in diabetic women is thought to be an index of psychological adjustment to chronic disease (Jensen, 1986). Somatic and autonomic neuropathy, which are the neurogenic causes of sexual dysfunction in diabetic men (Lin & Bradley, 1985), may be contributing to sexual dysfunction in women, but electrodiagnostic testing to confirm this is nonexistent. In conclusion, the literature reports conflicting results on the effect of diabetes and female sexual function.

Other Neurologic Diseases

Sexual dysfunction has been documented in women with other chronic neurologic diseases such as cerebrovascular accidents (Boldrini, Basaglia, & Calanca, 1991; Monga, Lawson, & Inglis, 1986), Alzheimer's disease (Derouesne, Guigot, Chermat, Winchester, & Lacomblez, 1996), and traumatic brain injury (Aloni & Katz, 1999; Sandel, Williams, Dellapietra, & Derogatis, 1996). Most of these studies examine the prevalence of sexual dysfunction in these diseases, without distinguishing gender-specific differences. Studying female sexual dysfunction (FSD) in disorders that are more prevalent in older populations such as cerebrovascular accidents and Alzheimer's disease is problematic, since the confounding factors of senescence make it difficult to attribute the sexual dysfunction to the disease process alone. Additionally, studying FSD in neurologic diseases resulting in global, diffuse, or poorly defined neuropathology (e.g., traumatic brain injury, Alzheimer's disease) is troublesome: The affected area(s) of the brain can be so variable that the possibility of drawing valid conclusions regarding the portion of the affected neuraxis that is disrupting sexual function is vastly diminished (Aloni & Katz, 1999). Although sexual dysfunction in these populations can be demonstrated, localizing the causative neurologic lesion(s) has been elusive.

TREATMENTS

Treatment for sexual dysfunction in women with neurologic disease is not disease specific. Given the irreversible nature of neurologic diseases, medical therapy specific for FSD in these patients is aimed at improving the local genital environment, maximizing genital sensation, reversing medication-related side effects, and, where possible, treating or stabilizing the patient's overall medical condition to improve her sense of well being. This approach assumes that there are no other reversible urogynecologic or other medical factors which may potentially cause the symptoms of FSD. Psychotherapy, with or without the partner, is frequently helpful even when organic causes for FSD are identified. This approach typically helps the woman and her partner deal with the loss of prior sexual functioning, develop emotional connections to support the relationship, and explore new possibilities of emotional and physical exchange.

In women who have experienced menopause, hormone replacement therapy (HRT) has been shown to improve the vascularity of vaginal tissue and increase lubricating capacity (Studd et al., 1977). Systemic estrogen replacement has not been demonstrated to have a direct effect on libido (Campbell & Whitehead, 1977; Studd et al., 1977), but the improved overall sense of well-being brought on with hormonal balance does seem to increase sexual desire (Heiman & Lentz, 1999). For women with difficulty in lubrication, either systemic or topical hormone replacement improves vaginal tissue integrity. Topical hormone therapy works more rapidly, and is indicated for those women who choose not to have systemic replacement due to increased risks of cancer (Genazzani & Ganbacciani, 1999). These preparations typically are in cream form, but there is a new estradiol-releasing vaginal ring (Estring) which has been shown to be as safe and efficacious as estrogen vaginal creams (Ayton, Darling, Murkies, Farrell, Weisberg, et al., 1996). The slow release mechanism allows for constant, topical administration of estradiol over 90 days.

There are numerous water soluble, topical preparations that can also be used for vaginal lubrication (K-Y jelly, Replens, etc.). They can be helpful in relieving discomfort with intercourse from vaginal dryness while waiting for estrogens to restore the vaginal epithelium. If a woman is contemplating pregnancy, the spermicidal effects of certain lubricants should be considered.

Androgens have been studied as a treatment for decreased libido in women. Sherwin, Gelfand, & Brender (1985) performed a prospective double-blind cross-over study in surgically menopausal women with injectable estradiol, testosterone alone or in combination with estradiol, and placebo. Estrogen alone had no effect on desire, arousal, or frequency of sexual fantasies. The androgen groups, however, had greater sexual desire, arousal levels, and sexual fantasies compared to placebo or estrogen alone; androgens did not impact on coital or orgasmic frequency. More recent work by Davis, McCloud, Strauss, and Burger (1995) involved a single-blind randomized trial in 34 postmenopausal women. They were given estradiol or estradiol plus testosterone implants. Sexual activity, satisfaction, and orgasm improved in both groups, but the latter group demonstrated greater improvement. In concert with other literature, the data on androgen replacement suggests improved sexual desire in women who have undergone menopause. How this information may relate to FSD in women with chronic neurologic disease is unknown.

Orgasmic disorders refer to the persistent delay or absence of orgasm. Certain classes of drugs are known to inhibit or delay orgasm, particularly antidepressant medications with peripheral anticholinergic activity or adrenergic antagonist effects (Heiman & Meston, 1997). Serotonin and dopamine availability are thought to impact on sexual functioning as well, but the mechanisms are not clear (Meston & Gorzalka, 1992). Selective seratonin reuptake inhibitors are commonly associated with absent or delayed orgasm (Modell, Katholi, Modell, & Depalma, 1997; Rosen, Lane, & Menza, 1999), and their use in women with neurologic disease may exacerbate existing sexual dysfunction. Additionally, any medication that has central or peripheral nervous system effects can potentially disrupt orgasmic capacity and libido. Many women with chronic neurologic disease are on medications that have CNS activity (e.g., antiepileptics, muscle relaxants), and these should be evaluated on an individual basis.

In the context of a chronic neurologic illness, inadequate sensory input to the central nervous system is likely a very prominent factor in FSD. For women who have decreased genital sensation, or who fail to orgasm because of inadequate genital afferent input to the CNS, use of vibrators may overcome the sensory deficit in some instances by providing genital stimulation at greater intensity. If one side of the body is less affected by the neurologic disorder than the other, concentrating tactile stimuli to the less affected side may be beneficial. Other behavioral modifications can be suggested by sexual therapists.

Recently, attention has been directed to the oral medications available for male sexual dysfunction and their possible role in the treatment of FSD. Sildenafil (Viagra[R]) is an inhibitor of phosphodiesterase type 5, and selectively inhibits cGMP catabolism in the smooth muscle of the erectile bodies in the penis (Boolell, Gepi-Attee, Gingell, & Allen, 1996). The resultant effect is that of increased blood flow into the penis, with ensuing penile erection in the context of sexual stimulation (Lue & Tanagho, 1987). In females, the clitoral bodies are composed of vascular tissue similar to that found in men. Decreases in clitoral and vaginal blood flow are thought to be potential causes of FSD (Berman, Berman, & Goldstein, 1999). With this rationale, sildenafil is being used in clinical studies for treatment of FSD. Recently, the first report was published following 30 postmenopausal women with FSD treated with sildenafil. Although some women reported changes in vaginal lubrication and clitoral sensitivity, overall sexual function in this cohort did not improve significantly with regular sildenafil use (Kaplan et al., 1999). Additional studies with sildenafil are currently ongoing; other medications in clinical trials for male impotence (e.g., apomorphine, phentolamine) are being evaluated in women as well (Berman et al., 1999). For women with neurologic disease, these medications can bypass efferent neural damage, thus facilitating the genital changes that occur with sexual arousal, but they cannot restore sensory loss. Expectations for these treatments are high, as judged by the extensive coverage in the lay press, but these hopes should be tempered with the recognition that what works in the male may not be appropriate in the female.

FUTURE RESEARCH IN FEMALE SEXUAL RESPONSE

Most literature on neurologic disease and sexual function has focused on the male sexual response. Because there are discrete, objectively measurable physiologic events in the male, not only can incidence and type of dysfunction be documented, but pathophysiologic data can be accrued as well. Investigations of female sexual dysfunction in neurologic disease have been primarily questionnaire-type studies, which vary significantly with regard to the types of questions asked and the reporting of the symptomatology. Studies using objective measures of sexual function include techniques such as vaginal plethysmography, labial thermometry, vital signs monitoring, and quantification of analgesia during genital self-stimulation (Komisaruk et al., 1997; Morrell et al., 1994; Sipski, Alexander, & Rosen, 1995; Slob, Koster, Radder, & van der Werff ten Bosch, 1990; Whipple, Gerdes, & Komisaruk, 1996). Because easily quantified physiologic events are lacking in the female, there are currently no standardized, readily available measures of female sexual responsiveness. Furthermore, the existing techniques to objectively assess genital responses in women do not necessarily correlate with an individual's subjective sexual fulfillment (Morrell et al., 1994; Slob et al., 1990). This creates a complex situation in studying female sexual responses in health and in disease. In the absence of a reliable, objective measure of sexual responsivity, physiologic studies are difficult to construct. Another problem in the study of FSD is the tendency of investigators to analogize the events that occur in the male with what occurs in the female. Extrapolation of some physiologic data may be valid, but with the differing anatomy, neuroanatomy, and hormonal milieu of each gender, physiologic differences outweigh the similarities.

Recently, research trends have emphasized the vasogenic aspects of the female sexual response, with extrapolation of what is understood of the male response to the female (Berman et al., 1999). Judging by the significant negative impact of neurologic disease on female sexual function, and recognizing that the genital vascular responses are a direct result of neurologic activity, the role of neurogenic factors should not be discounted. From a neurologic standpoint, there are three research areas that need to be approached.

Neuroanatomy

More study is needed in humans to better define the neuroanatomic pathways responsible for sexual responsiveness. Much of the existing data is based on animal studies (Berkley, Hotta, Robbins, & Sato, 1990; Peters, Kristal, & Komisaruk, 1987), and is not necessarily applicable to the human condition. Human studies are needed not only to define pathways, but to document the variability of peripheral innervation that necessarily exists. Neuroanatomic investigations can be conducted through dissection (Baskin, Erol, Li, Kurzrock, & Cunha, 1999; O'Connell, Hutson, Anderson, & Plenter, 1998) or using functional imaging studies such as PET scanning (Komisaruk et al., 1997; Stoleru et al., 1999).

Neurophysiology

Concomitant with a better understanding of the neuroanatomy of female sexual function, electrodiagnostic studies can be applied to confirm reflex pathways and document pathology. Electrodiagnosis, the recording and analysis of responses of nerves and muscles to electric stimulation, has not been exploited to its full potential in the female urogenital system. Although the concept of female genital electrodiagnostic testing is not new, it has been only recently that this discipline has gained attention (Benson, 1990; Haldeman, Bradley, Bhatia, & Johnson, 1983; Opsomer, Guerit, Wese, & van Cangh, 1986).

Neuropharmacology

Studies are needed not only in neurotransmitters and receptors that modulate the female sexual response (Hauser-Kronberger et al., 1999; Ottesen et al., 1987), but also in pharmaceutics that reverse the neural/axonal damage incurred by neurologic disease, which may have a therapeutic effect for the patient with sexual dysfunction (Apfel, 1999; Stevens et al., 1995).

In the treatment of female sexual dysfunction in chronic neurologic disease, the assessment of the primary disease is an important factor in understanding the nature of the sexual dysfunction, as well as in deciding what approach to take in therapy. A collaborative effort between the neurologist, who has the ability to translate the nervous system pathophysiology into neuroanatomic and neurophysiologic changes; the gynecologist and urologist, who are familiar with the gross and surgical anatomy of the female genitalia, and the pertinent hormonal milieu; and the mental health practitioner, who has the most historical experience investigating and treating female sexual dysfunction would result in increased understanding in this multifaceted field of medicine.

CONCLUSION

When a woman with a chronic neurologic disease is still sexually active, or desires to have a sexual relationship, it is important to openly acknowledge her sexuality and how it can be affected by the disease. This is a commonly neglected component of the patient's care, and may be an important element in her ability to cope with her illness. Recognition of FSD in these women, as a consequence of both physiologic and psychological causes, is crucial to the holistic care of their disease. Disease-specific treatment is limited at this time, due to a lack of knowledge about the anatomy and physiology of the female sexual response. In comparing gender-specific literature in sexual physiology, there has not been the same amount of energy devoted to the study of female sexual function and dysfunction as there has been in the male. In large part, this may be due to the difficulties in developing objective, specific, and universally accepted means of measuring physiologic parameters of female sexual responsiveness. Continued research in this field is crucial, especially in the areas of neuroanatomy, neurophysiology, and neuropharmacology. Investigations of female sexual dysfunction in women with neurologic disease can help to define the portions of the neuraxis that affect sexual function. Collaborative efforts between different disciplines are sorely needed to take advantage of the fruitful discoveries in the area of female sexual function and dysfunction.

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Manuscript accepted April 26, 2000

Claire C. Yang University of Washington

Address correspondence to Claire C. Yang, MD, University of Washington, Department of Urology, Box 356510, Seattle, WA 98195.

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