Women's Sexual Function and Dysfunction. Irwin Goldstein MD

Neurophysiology of female genital sexual response

François Giuliano, Véronique Julia-Guilloteau

Introduction

Anatomic structures in the genital apparatus that are involved in the female genital response include the vestibular bulb, the vagina, the uterus and the pelvic-perineal musculature. The vulva, including the portions of the female genital apparatus that are externally visible in the perineal region, consists of the mons veneris, the labia minora and majora, the clitoris, the vestibule, the vaginal orifice, and the urethral meatus.

Female genital sexual response consists of local arousal and orgasm. Peripheral genital sexual arousal may be defined as a genital vasocongestion that is controlled by the autonomic nervous system. It involves an increase in pelvic-perineal blood flow leading to the engorgement with blood of (1) the labia; (2) the vaginal wall, resulting in lubrication; and (3) the clitoral erectile tissue.1 From a neurophysiologic genital aspect, orgasm involves rhythmic contractions of the pelvic striated circumvaginal musculature, often with concomitant uterine and anal contractions; therefore, orgasm involves both smooth and striated muscles.2-5

Anatomic structures involved in female genital sexual response are innervated by autonomic and somatic nerves. These include (1) the pelvic nerve issuing from the intermedio- lateral cell column of S2 to S4 levels of the spinal cord, also called the parasympathetic nucleus; (2) the hypogastric and the lumbosacral sympathetic chain conveying sympathetic fibers originating from both intermediolateral cell column and dorsal gray commissure of thoracolumbar levels of the spinal cord (T12-L2); (3) the pudendal nerve (somatic) with cell bodies of the motoneurons located in Onuf’s nucleus divided in the rat into dorsomedial and dorsolateral nuclei in the ventral horn of the sacral spinal cord (S2-S4); and (4) the vagus nerves issuing from the nucleus tractus solitaris.

Afferent pathways consist of pudendal, pelvic, and hypogastric nerves and the lumbosacral sympathetic chain. They relay information to the dorsal horn, medial, central, and lateral gray matter of the lumbosacral spinal cord.6-8 In addition, vagal afferent fibers convey sensory information from the genital apparatus directly to the nucleus tractus solitaries.

During sexual genital response, the genital apparatus can be considered as an effector and a receptor. Afferent pathways play a crucial role in participating in the facilitation and/or the triggering of both peripheral arousal and orgasm. They convey sensory information from the periphery to the central nervous system through the spinal cord, which represents a relay to supraspinal sites via the spinothalamic and spinoreticular pathways.

Peripheral neurophysiology

Afferent pathways/sensory innervation of the genital apparatus

There is little information available about the exact role of afferent fibers innervating the female genital tract. It appears that the sensitivity and the responses to local stimuli are variable, depending on anatomic structures, that is, the vagina, clitoris, cervix, and uterus. Different sensitivities are defined in function of the different types of stimuli: mechanosensitivity (pressure stimulus), chemosensitivity (irritant stimulus, e.g., bradykinin), and thermosensitivity (cool or warm stimulus). Afferent fibers conveying sensory information are generally divided into three types: A-beta fibers, the largest fibers, which mediate touch, mild pressure, and vibration; A-delta fibers, which mediate cold and pain sensations; and C-fibers, the smallest fibers, which mediate pain and temperature sensations. Sensitivity can be divided into somatic sensitivity for skin and articulations and visceral sensitivity for internal organs. Genital sensitivity includes both somatic and visceral sensitivities, depending on location of the anatomic structure (outer versus inner). Moreover, the distinct physiologic role of each structure, such as the clitoris, vagina, and uterus in sexual arousal, orgasm, and parturition, determines the nature of neural afferent inputs (sensation or/and nociception).

Clitoral stimulation is the main source of sensory input for eliciting orgasm.9-12 In female cats, the afferent fibers from the clitoris travel exclusively in the pudendal nerve since pudendal nerve transection eliminates 99% of the labeled cells in the sacral dorsal root ganglia following antegrade axonal transport from the clitoris. In contrast, 40% of neural cell bodies of the S1 dorsal root ganglion whose fibers are conveyed by the pudendal nerve innervate the clitoris. In the S2 dorsal root ganglia, only 5% of neural cell bodies whose fibers are conveyed by the pudendal nerve are clitoral afferent fibers.13 In female cats, the conduction velocity of myelinated clitoral afferent fibers ranges from 5.2 to 30m/s but is mainly 10-15 m/s. This conduction velocity is slightly slower than skin afferent pathways,14 suggesting that although the clitoris is an external genital organ, its sensitivity is close to that of the skin. In women, Vardi et al.15 have characterized the clitoral sensitivity in response to different applied stimuli. Stimulation of the woman’s clitoris can be induced by temperature changes (cold and warm) and vibrations.

Generally, it may be hypothesized that coital orgasm is triggered by stimulation of internal genital organs; i.e., the vagina, cervix, and uterus. The exact neurophysiologic support for the coital orgasm is less clear than for the one elicited by clitoral stimulation.

In female cats, vaginal afferents travel in the pelvic nerve.16 In female rats, the conduction velocities of afferent units from the uterus or the vagina are always less than 2 m/s, corresponding to C-fiber conduction velocity. Low or no spontaneous activity is observed. The receptive fields of the vaginal afferent fibers increase from the vaginal orifice to the vaginocervical junction.17 In female rats, the hypogastric nerve afferent fibers innervate the uterus, the cervix, and the ovaries. These afferent fibers carry only noxious information18 (Fig. 5.3.1).

The urogenital reflex intends to mimic the human orgasmic response by applying a mechanical stimulation to the urethra. An experimental model has been developed in anesthetized female rats. The urogenital reflex can be elicited only after acute spinalization of female rats. Thus, it is suggested that to observe this reflex, it is necessary to cut descending inhibitory inputs.19 The urogenital reflex includes rhythmic contractions of the vagina, the uterus, and the anal sphincter, as well as the striated pelvic musculature. Stimulation of the urethra may mimic stimulation of the anterior wall of the vagina, which is the area with the highest “erotic” sensitivity. Indeed, the anterior wall of the vagina has a denser innervation than the posterior wall, and the distal area has more nerve fibers than the proximal.20 In the female rat, vaginocervical stimulation induced by mechanical probing (300 g) against the vaginal cervix elicits a variety of responses, including analgesia, pupil dilation, increase in blood pressure and heart rate, flexor inhibition, and behavioral responses such as facilitation of lordosis.21 Although this stimulation is nonphysiologic, this experimental model allowed observation of the role of pelvic, hypogastric, pudendal, and vagus nerves in the female sexual response. Indeed, bilateral transection of pelvic, hypogastric, and pudendal nerves does not affect pupil dilation and analgesia. Conversely, these two responses were reduced after transection of the vagus nerve, suggesting its role in the transmission of the messages in response to vaginocervical stimulation.

Despite the fact that the vagus nerve is involved in the transmission of sensory information from the female genital organs to the nucleus tractus solitaries, its exact role in the female genital response remains unclear. It is not known whether the vagus nerve represents a supplemental afferent pathway to the spinal system or is activated only after spinal injury. Indeed, it has been reported that in spinal cord-injured women, orgasms induced by vaginal and cervical selfstimulations can occur.22,23 These data suggest that genital information may be sent to supraspinal centers via the vagus nerve. It is proposed that the afferent vagal pathway may be involved in the central feeling of orgasm in women with complete spinal cord transection, or may exert a facilitatory role in addition to the spinal to brain pathway in normal women. In contrast, the urogenital reflex is not abolished after transection of the vagus nerves.

Figure 5.3.1. Afferent innervation involved in female genital sexual response.

Overall, the pudendal nerve that conveys sensory information from the vulva and the striated pelvic-perineal musculature to the spinal cord plays a central role in the occurrence of clitoral orgasm. The pelvic and hypogastric nerves convey sensory information from the internal pelvic organs; they may have a role in “coital orgasm”.

Efferent pathways

The parasympathetic pathway which innervates the genital apparatus is responsible for clitoral swelling during sexual excitation as well as vaginal congestion, and lubrication and lengthening of the vagina.25,26 In anesthetized rabbits, electrical stimulation of the pelvic nerve elicits an increase in vaginal blood flow, wall pressure and length as well as intraclitoral pressure and clitoral blood flow. In contrast, electrical stimulation of the pelvic nerve decreases intravaginal luminal pressure.27 In the rat, clitoral and vaginal blood flows increase after electrical stimulations of both the clitoral and pelvic nerves.28,29

In spinalized female rats, the urogenital reflex elicited by urethral distention comprises vaginal and uterine contractions accompanied by rhythmic contractions of the vaginal and anal orifices. The urogenital reflex implicates several efferent nerves, since firing of pelvic, hypogastric, pudendal, and cavernous nerves has been recorded during the reflex.

Activation of the sympathetic nervous system, which occurs during the later stages of sexual arousal and orgasm, is responsible for an increase in heart rate and blood pressure in women.30 The effects of sympathetic nervous system activation on sexual arousal have been examined during exercise, which is accompanied by sympathetic nervous system activation. Meston and Gorzalka31 have demonstrated that, in women, physiologic sexual arousal is facilitated by acute and intense exercise in the presence of an erotic stimulus. In laboratory conditions after exercise, an increase in vaginal pulse amplitude and vaginal blood volume have been observed, suggesting a facilitatory effect of sympathetic activation on physiologic sexual arousal. The time course of the facilitatory effect of sympathetic nervous system activation on sexual arousal in women has been determined: sexual arousal is not increased by immediate sympathetic activation (5 min after exercise), whereas delayed and residual sympathetic activation facilitates women’s sexual arousal.32 In female rats, peripheral administration of guanethidine (a postganglionic noradrenergic blocker) suppresses lordosis and proceptive behavior. These results suggest that the sympathetic nervous system is implicated in female sexual behavior.33

The pudendal nerve innervates the striated pelvic-perineal musculature. Its recruitment is responsible for the rhythmic contractions of these muscles occurring during orgasm through a reflex arc handled at the sacral spinal cord level. The motor innervation of perineal muscles plays an additional role in the sexual response in women, because voluntary contractions of these muscles may enhance arousal and contribute to the feeling of pleasure during sexual intercourse.34

Central neurophysiology

Spinal cord

Genital arousal and genital physiologic events, which occur during orgasm, are processed at the spinal cord level. This theory is based on (1) clinical studies reporting that in laboratory conditions genital stimulation elicits orgasm in spinal cord-injured women when the sacral reflex arc is intact35 and (2) the occurrence of the urogenital reflex in spinalized female rats at the T8 level of the spinal cord.19

The spinal cord is an integration site for afferent information from the periphery and modulation from supraspinal origin, including both excitatory and inhibitory inputs.

Using the transneuronal retrograde tracing technique with pseudorabies virus, the spinal neurons destined to the clitoris have been identified in rats.33,36 The major input to the clitoris originates from the lumbosacral spinal cord (L5-S1), with a strong labeling present on both sides of the lateral gray in the region of the parasympathetic preganglionic neurons of the pelvic nerve and in the dorsal gray commissure. Fewer labeled cells were found in the T13-L2 spinal segments, where the sympathetic neurons of both the hypogastric nerve and the lumbosacral paravertebral sympathetic chain are located. The retrograde transneuronal tracing technique was also used to identify pathways to the cervix in rat. Retrograde transport from the cervix occurs via the hypogastric and pelvic nerves. In addition, intraspinal circuitry has been suggested between the thoracolumbar and lumbosacral levels.37 Such an intraspinal organization is probably involved in the coordination between parasympathetic and sympathetic output to the genital apparatus. This leads to a discussion as to whether a discrete group of spinal cells, designated as the lumbar spinothalamic cells, which have been demonstrated in males as a spinal ejaculation gener- ator,38,39 plays a major role in females. The lumbar spinothalamic cells are not activated during vaginocervical stimulation in females,38,39 but are activated during urogenital reflex in female rats.24

Ascending and descending pathways

Sensory information is relayed through the spinothalamic and spinoreticular pathways to the brain. Fast myelinated fibers travel in the dorsal columns and dorsal lateral quadrant and terminate in the thalamus. Spinoreticular fibers cross to the opposite side of the cord and travel in the lateral spinal columns, terminating in brainstem reticular formation.40

Descending information from the brain also travels in the dorsal and dorsolateral white matter and enters into the spinal gray matter.

Spinal interneurons

Spinal interneurons relay afferent input from the genital apparatus to the efferent somatic and autonomic spinal neurons destined to the anatomic structures participating in the female genital sexual response. They also receive projections from the supraspinal structures and may be a site for modulating the activity of the spinal nuclei controlling the peripheral events occurring during female sexual response. These interneurons are located in and around the intermediolateral cell column and in the medial gray forming a column of neurons through segments T13 to S1. In cats, electrophysiologic recordings suggested that spinal interneurons in the medial gray are involved in the mediation of pelvic and perineal stimulation.13,41,42

The role of the spinal cord in female sexual response has been investigated in women with spinal cord injury. It is common that women with spinal cord injury have difficulties in achieving orgasm.43 Systemic modifications associated with orgasm, such as blood pressure, heart rate, and respiratory rate fluctuations, are similar in women with and without spinal cord injury.44 Women with complete spinal cord injury at midthoracic level still present perceptual responses to vaginal and/or cervical self-stimulation.22

Overall, the spinal cord is a key structure in the control/com- mand of the female genital response. It receives genital afferent input and contains neurons projecting to every anatomic genital element participating in the sexual response. In addition, spinal interneurons may (1) connect afferent and efferent pathways responsible for sexual response by local stimulation, suggesting that orgasm is at least partly a spinal reflex and (2) may be responsible for the coordination between various components of the sexual response. Last but not least, the spinal cord receives the inhibitory/excitatory projections from the brain.

Brain structures

Anatomic organization

Descending projections from the brainstem, pons, and hypothalamus reach the spinal nuclei controlling the genital sexual response. Thus, spinal autonomic preganglionic neurons as well as motoneurons receive direct monosynaptic inputs from a variety of nuclei in supraspinal structures. In particular, several brainstem nuclei send projections to the spinal sympathetic and parasympathetic nuclei controlling sexual functions. In rats, the thoracolumbar cell column (intermediolateral cell column), the dorsal gray commissure, the sacral parasympathetic nucleus, and the pudendal motoneurons receive abundant serotoninergic innervation from raphe nuclei.34,45-48 The same structures are also innervated by the noradrenergic nuclei A5, A6 (locus coeruleus), and A7.49,50 Terminal projections from the A11 dopaminergic cells group also reach the intermediolateral cell column and the dorsal gray commissure down to the sacral levels.51 Injection of pseudorabies virus into the rat clitoris labeled neurons in the paragigantocellularis nucleus (nPGi), raphe pallidus, raphe magnus, Barrington’s nucleus, ventrolateral central gray, hypothalamus and the medial preoptic area.33,36 By the same technique, neurons in the ventrolateral nucleus of the hypothalamus are labeled after virus injection into the uterus and the vagina.52

Functional data

In female rats, the ventromedial nucleus of the hypothalamus has been shown to play a pivotal role in the control of lordosis, which is a supraspinal reflex leading to arching of the back and raising of the head. Lordosis is a behavioral marker for receptivity; this is a reflex activity occurring during copulation in this species. The clinical extrapolation of female rat lordosis is highly questionable. To date, there has been no demonstration that lordosis is accompanied by sexual arousal.

It was demonstrated that sexual stimulation induces c-fos gene expression within specific regions in the forebrain of female rats. Vaginocervical stimulation or copulation with intromission elicits c-fos expression in the medial preoptic area, the bed nucleus of the stria terminalis, the paraventricular hypothalamus, the ventromedial nucleus, the medial amygdala, and the ventral premammillary nuclei.53,54

The medial preoptic area is an important structure in controlling female sexual response. In anesthetized female rats, electrical stimulation of the medial preoptic area resulted in an increase in vaginal blood flow and wall tension.29 Neuronal pathways from the medial preoptic area interconnect with the periaqueductal gray, which plays a facilitator role in lordosis.53

In contrast, the paragigantocellularis nucleus inhibits the urogenital reflex. Because this nucleus receives sensory information from the genital apparatus and sends descending projections to the spinal nuclei controlling the female genital sexual response, it is proposed that this structure inhibits female peripheral sexual function.

Brain imaging by positron emission tomography studies in humans have revealed the structures implicated in the female sexual response. During orgasm, there is enhanced activation in the paraventricular hypothalamus, the periaqueductal gray, the amygdala, the hippocampus, the striatum, the cerebellum, and different regions of cortex.55 During self-stimulation, nucleus tractus solitaries, somatosensory and motor cortices, the thalamus, and sensory areas of the spinal medulla are activated. However, it seems that visual sexual stimulation (frequently used to evaluate female sexual arousal) does not activate the same brain structures implicated in orgasm. Several studies have reported the differences between men and women in brain structure activation in response to sexual arousal. Generally, brain imaging studies showed that during sexual arousal the amygdala and the hypothalamus are more strongly activated in men than women.56

Conclusion

We have attempted to summarize information regarding the neural control of the female genital sexual response to sexual stimulation. We have not discussed the crucial issue of hormonal status, which strongly interacts with the neural command of female sexuality along the entire neuraxis. Another chapter is dedicated to the key role of hormones. On the other hand, the neurochemical support of female sexuality has not been well described. There is a tremendous need for research in this area, particularly at the central nervous system level. Indeed, better knowledge of the central neurotransmitter system involved in the command of sexual response would facilitate design of pharmacologic interventions to restore impaired sexual function in women.

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