Women's Sexual Function and Dysfunction. Irwin Goldstein MD

Vascular physiology of female sexual function

Annamaria Giraldi, Roy J Levin

Introduction

During sexual stimulation, the female sexual arousal response is elicited by sensory stimulation as well as central nervous system activation, resulting in increased genital blood flow and, to some extent, relaxation of genital smooth muscle structures. This culminates in a series of vasocongestive as well as neuromuscular events leading to physiologic changes, including engorgement of the labia, vaginal lubrication, and increased length and width of the clitoris.

Dickinson,1 Kinsey et al.,2and Masters and Johnson3 described the human female sexual arousal, largely phenomenologically, with few quantitative aspects. For many years, most advances in our knowledge about the human female sexual arousal response have been from methods that measure changes in genital functions, primarily giving information about physiologic mechanisms in the sexual arousal response very often from isolated organ models, and not “whole” women. The reason for the lack of studies on female sexual arousal may rely on the taboo and ethical considerations against laboratory use of women for studies on human sexual arousal. However, during the last 10 years, there has been an increased focus on studies on female sexuality and more laboratory experiments with quantitative data. Still, much of our knowledge about basal vascular and tissue physiology involved in the female sexual arousal response derives from animal models, which can help to elucidate similar mechanisms in the human but never can replace human measurements.

This chapter describes the physiologic mechanisms behind these vasocongestive and neuromuscular events during the female sexual arousal response, based on data from both animal and human studies.

Blood supply of the female genitals

The genitals have a rich arterial blood supply. The labia are supplied from the inferior perineal and posterior labial branches of the internal pudendal artery as well as from superficial branches from the femoral artery. The clitoris receives its arterial blood supply mainly via the ileohypogastric pudendal arterial bed. After the internal iliac artery has given off its last anterior branch, it transverses Alcock’s canal (pudendal canal) and terminates as the common clitoral artery, which gives off the clitoral cavernosal arteries and the dorsal clitoral artery. The proximal (middle) part of the vagina is supplied by the vaginal branches of the uterine artery and the hypogastric artery. The distal part of the vagina is supplied by the middle hemorrhoidal and clitoral arteries.

During female sexual arousal, the blood flow to the genitals is increased, leading to vasocongestion, engorgement, and lubrication.4-6 In a study on 48 pre- and post-menopausal women, Berman et al. demonstrated that sexual stimulation resulted in significant increases in clitoral, labial, urethral, and vaginal peak systolic velocity and end diastolic velocity as a measure of arterial blood flow7 (Table 5.4.1). In addition to the increased blood flow, the venous drainage is most probably reduced, resulting in vasocongestion and genital engorgement, clitoral tumescence, and increased genital sensitivity and vaginal lubri- cation.8

The data of Table 5.4.1 objectively illustrate the physiologic changes during female sexual arousal. In the next sections, the consequences of the increased genital blood flow will be described in more detail (Fig. 5.4.1).

Vaginal lubrication, basal and during sexual arousal

Vaginal lubrication during sexual arousal is a consequence of increased vaginal blood flow to sexual stimuli. The vagina consists of a tube of smooth muscle lined on the luminal side by squamous epithelial without glands. The smooth muscle is set in a bed of the pelvic striated muscle (Fig. 5.4.1).

Table 5.4.1. Mean pre- and poststimulation clitoral, labial, urethral, and vaginal arterial blood flow measurements

   

Blood flow

 

Pre-

stimulation

Post-

stimulation

 

EDV (cm/s)

PSV (cm/s)

EDV (cm/s)

PSV (cm/s)

Clitoral

3.35 ± 2.24

12.39 ± 6.22

8.20 ± 5.68*

22.00 ± 6.22*

Left labial

4.07 ± 3.12

16.91 ± 9.52

12.58 ± 14.90*

27.18 ± 18.06*

Right labial

3.21 ± 2.20

15.20 ± 7.08

6.94 ±4.10*

25.31 ± 12.32*

Urethral

2.74 ± 2.07

15.10 ± 7.77

7.31 ± 4.50*

29.00 ± 16.64*

Left vaginal

4.12 ± 3.30

20.33 ± 10.99

9.51 ± 5.97*

39.96 ± 20.69*

Right vaginal

5.56 ± 4.60

18.32 ± 10.31

9.70 ± 5.60*

31.41 ± 12.80*

PSV = peak systolic velocity; EDV = end diastolic velocity. * Statistically significant increases in PSV and EDV from pre- to post-stimulation at the p <0.05 level.

Modified from Berman et al.7

During sexual quiescence, the human vagina is a potential space with an H-shaped transverse cross-section and an elongated S-shaped longitudinal section. The anterior and posterior walls of the vagina are normally collapsed and touch each other. Nevertheless, they do not adhere, as they are covered with a thin layer of basal fluid allowing them to separate easily. No glandular elements have ever been identified in the normal human vagina. The fluid is a mixture of secretions from the whole female genital tract, mainly a vaginal plasma transudate mixed with desquamated cervical and vaginal cells and cervical secretion (see reviews^10). The vaginal fluid is a transudate formed from the blood circulating through the capillaries supplying the vaginal epithelium. A plasma filtrate from the blood leaks out of the capillaries into the interstitial tissue space. In the vagina, the fluid then passes through the epithelium. In the sexually unstimulated state, the vaginal fluid has a higher K+ and lower Na+ concentration than plasma throughout the phases of the menstrual cycle.11,12 The basal transudate that percolates through the epithelium is modified by the cells’ capacity to reabsorb Na+ ions.13 During nonsexual stimulation, the slow passage through the epithelium results in sufficient contact time, making the cells capable of reabsorbing Na+ by the vaginal epithelium and acting as the main determinant of reabsorption of vaginal fluid through the mechanism of ionic driving force. This leads to a condition in the basal condition where the vagina is just moist, but not lubricated enough to allow penetration without pain. The circulation to the nonsexually aroused vagina is low,8 resulting in a hypoxic lumen with a low oxygen tension.8,9 During sexual arousal, the blood flow to the vaginal epithelium is rapidly increased as a consequence of neural innervation via the sacral anterior nerves (S2-S4).14,15 The increased flow results in an increased ultrafiltrate percolating between the vaginal epithelial cells and saturating their limited reabsorptive Na+ transfer capacity. As a consequence of this, the fluid accumulates on the vaginal surface as a clear, slippery, and smooth lubricant, moistening the vagina so painless penile penetration and thrusting is possible. In addition to the increased blood flow, the venous drainage is most probably reduced, enhancing the vasocongestion.8 When the sexual stimulus stops, the neural stimuli for the vasodilation also stop, leading to a slow return to basal level of the vaginal blood flow and transudation.

Figure 5.4.1. Vaginal wall showing main structural features. With permission from Wagner et al.

Clitoral engorgement during arousal

The clitoris is an erectile organ similar to the penis. It consists of three parts: the outermost glans, the middle corpus, and the innermost paired crura. The paired crura are homologous to the male corpora cavernosae. They are composed of trabecular smooth muscle and collagen connective tissue forming a sinusoidal structure surrounded by a fibrous sheath, the tunica albuginea.16 During sexual arousal, the blood flow to the clitoris is increased, the trabecular smooth muscle in the clitoris is relaxed, and thereby the intracavernous clitoral pressure rises. As the tunica albuginea in the clitoris is unilaminar, in contrast to the penis with a bilaminar structure, the fascia is more elastic and thus no mechanism for venous occlusion occurs in the clitoris. Consequently, the clitoris shows increased tumescence and becomes engorged, but has not a true “erection” (stiffness) during arousal, as has been elegantly shown by Maravilla and coworkers, using magnetic resonance imaging (MRI) to visualize the engorgement of the genitalia during sexual arousal.4-6

Preferential innervation of importance for the female genital arousal response

The neurotransmitters that modulate vaginal, clitoral, and vascular smooth muscle tone are currently under study. The neural control regulating the female genital response is poorly investigated, and is therefore less understood than in the male. Most of the investigations examining the neural control have been done in animals; primarily rodents, and only few human studies exist. Studies on mechanisms of genital arousal include: the regulation of vaginal blood flow; clitoral, labial, and vestibular bulb engorgement; and studies on contraction and relaxation of the vaginal smooth muscle wall. The role of contraction and relaxation of the vaginal smooth muscle wall in the genital arousal response is still debatable. Many in vitro studies have focused on vaginal tone and its regulation, as it is an easy end organ to study and exhibits basal smooth muscle properties, which may be comparable with that of smooth muscle in the genital vasculature and clitoris.

Autonomic neurotransmitters in the female genital arousal response

Acetylcholine and noradrenaline

Adrenergic and cholinergic neurotransmitters have been identified in the postganglionic fibers to the vagina and the clitoris, primarily in animal models,17-23 just as alpha-adrenergic receptors have been demonstrated biochemically and functionally in the rabbit vagina.20,21

Limited data exist on the presumed inhibitory effect of adrenergic stimulation on the female sexual genital response. In vitro experiments on rat and rabbit vaginal and rabbit clitoral smooth musculature show contractile response to adrenergic stimulation.24-26 In a pilot study, oral phentolamine was administrated to postmenopausal women with female sexual arousal disorder. The results indicated a moderate effect on subjective and objective parameters of sexual arousal.27 Unfortunately, it was impossible to discriminate between peripheral and central effects in the study. Meston and colleagues interpreted their photoplethsymographic evidence for a facilitatory role of peripheral adrenergic activation on genital arousal in women. Ephedrine (50 mg), an alpha- and beta-adrenergic agonist, facilitated vaginal photoplethysmograph measures of sexual arousal in a randomized, controlled trial on 20 women.28

The role of noradrenaline (norepinephrine) in the control of clitoral tumescence is indirect and illustrated only by case reports on treatment of so-called “clitoral priapism” with injection of adrenergic agonists.29,30

Despite the rich cholinergic innervation, the role of acetylcholine is uncertain. In the in vivo animal model described by Giuliano et al.,31 intravenous injection of atropine only slightly decreased the vaginal blood engorgement induced by stimulation of the pelvic nerve. In the same model, intravenous atropine decreased vaginal smooth muscle contractions, also induced by pelvic nerve stimulation. In a small uncontrolled study on six women, intravenous injection of atropine had no effect on vaginal blood flow during masturbation.32

Nonadrenergic, noncholinergic neurotransmitters/mediators

A great variety of nonadrenergic, noncholinergic neurotransmitters/mediators have been identified in the female genital tract, mainly in animal models. In animal studies on the vagina and its vasculature, vasoactive intestinal polypeptide, nitric oxide synthase (producing nitric oxide), neuropeptide Y, calcitonin gene-related peptide, substance P, pituitary adenylate cyclaseactivating polypeptide, helospectine, and peptide histidine methionine have all been identified and localized.19,20,23,25,33-40

In humans, vasoactive intestinal polypeptide, neuropeptide Y, adenylate cyclase-activating polypeptide, nitric oxide synthase, and calcitonin gene-related peptide immunoreactive nerves have also been identified and localized in the vagina.41-45

In the tissue from pre- and post-menopausal women, Hoyle et al.44 demonstrated a dense innervation of the vaginal vasculature (arteries, veins, and subepithelial plexuses); most abundant were neuropeptide Y and vasoactive intestinal polypeptide immunoreactive fibers, and less abundant were nitric oxide synthase, calcitonin gene-related peptide and substance P fibers. In the postmenopausal tissue, little or no nitric oxide synthase was found. Human studies are crucial. The major drawback of these studies is the fact that the tissues have been obtained from women undergoing hysterectomy, and therefore represent tissue from the proximal part of the vagina, which is the less innervated and of different embryologic origin from the denser innervated distal part,46 which may be of more importance in the physiologic sexual arousal response. An exception is the study of Jorgensen et al., who demonstrated neuropeptide Y immuno- reactivity in both the proximal and distal part of the human vagina as plexuses of nerve fibers beneath the vaginal epithelium in relationship to the small vessels.41

In the human clitoris, immunohistochemical studies on a few subjects have demonstrated vasoactive intestinal polypeptide, peptide histidine methionine, neuropeptide Y, calcitonin gene-related peptide, and substance P immunoreactive nerves,47 and one human case study demonstrated nitric oxide- containing nerves in the clitoris.48

Other signal transduction systems have been investigated. In cell cultures from human and rabbit vaginal smooth muscle, the signal transduction molecules, cyclic adenosine monophosphate and cyclic guanosine monophosphate have been studied. In the vaginal smooth muscle cells, cyclic adenosine monophosphate was increased by prostaglandin E1, and isoproterenol and cyclic guanosine monophosphate by sodium nitroprusside, a nitric oxide donor, suggesting that these signal transduction pathways are of importance for regulation of vaginal smooth muscle tone. Furthermore, sildenafil enhanced the intracellular accumulation of cyclic guanosine monophosphate in the human and rabbit vaginal smooth muscle cells.49

In the human vagina, phosphodiesterase type 5 expression has been demonstrated in the anterosuperior vaginal wall.50

The role of nonadrenergic, noncholinergic transmitters in the arousal response

Very little is known about the role of these neurotransmit- ters/mediators in the regulation of the genital arousal response in females, as the demonstration of their existence in the genital tract gives no information as to their functional roles in the physiology and pathophysiology of the genital arousal.

Vasoactive intestinal polypeptide

Vasoactive intestinal polypeptide has traditionally been considered to be the most important neurotransmitter in the regulation of human vaginal blood flow in the sexual arousal response. This assumption is based on (1) the high concentration of vasoactive intestinal polypeptide in the tissue of the genital tract, (2) the close association with the genital vasculature and vasoactive intestinal polypeptide-containing nerve fibres, (3) the observation that sexual arousal in women increases the level of vasoactive intestinal polypeptide in the plasma and (4) that intravenous and subepithelial administration of vasoactive intestinal polypeptide was able to increase vaginal blood flow in women.51 However, these are only indirect evidence, and further clinical studies have to be performed in order to obtain more information. The role of vasoactive intestinal polypeptide in the physiologic arousal response still needs to be investigated further.

Nitric oxide

During the last few years, the role of nitric oxide in the arousal phase has been studied with more interest, partly based on the knowledge from males, where it is known to play a crucial role for the erectile response. New in vivo models on rats, rabbits, and dogs have made it possible to investigate vaginal and clitoral blood flow, vaginal oxygen tension, and temperature and vaginal luminal pressure as indices of sexual arousal.31,52-56 In the in vivo animal models, pelvic nerve stimulation increases vaginal blood flow and temperature as well as clitoral blood flow.31,53,56 Stimulation of the paravertebral sympathetic chain reversed the pelvic nerve stimulation-induced effect in the rat.31 In both the rabbit and dog model, the phosphodiesterase type 5- inhibitors sildenafil and vardenafil, respectively, enhanced the pelvic nerve stimulation-induced vaginal and clitoral blood flow, indicating that the nitric oxide/cyclic guanosine monophosphate pathway is involved in the physiologic mechanism of female genital arousal.57,58

A role of the nitric oxide/cyclic guanosine monophosphate system on clitoral tumescence is further indicated by in vitro animal experiments. In rabbit clitoral corpus cavernosum, inhibition of nitric oxide synthase dramatically abolishes electrically stimulated relaxations, whereas sildenafil augments the relaxations.24,59,60 In human clitoral tissue, sildenafil has been demonstrated to inhibit phosphodiesterase type 5,61 and immunohistochemical studies have identified nitric oxide synthase immunoreactive nerve bundles within the glans and corpora cavernosa of the clitoris.62 Clinically, sildenafil has been shown to enhance vaginal engorgement measured by photoplethysmography during erotic stimulus in healthy women without sexual dysfunction.63 Clinical trials have been performed in order to investigate a possible role of sildenafil in treatment of female sexual dysfunction,64-66 but the efficacy of sildenafil in the treatment of female sexual dysfunction is still under debate, as the results were not very promising.

There are several indications of a role of the nitric oxide/cyclic guanosine monophosphate system in the genital arousal response, but the exact role in the normal arousal response still needs to be investigated further.

Pathophysiologic factors that may influence the physiologic genital arousal response

Diabetes

In rat models it has been shown that diabetes mellitus (type 1) induces vaginal fibrosis, measured as transforming growth factor beta expression in collagen connective tissue, fibroblasts, and smooth muscle fibers,67 and that the nitrergic-dependent relaxation of vaginal tissue is impaired during the diabetic state.25 Park and colleagues also have demonstrated that type 1 diabetes mellitus, in the in vivo rabbit model, produces significant adverse effects on the hemodynamic mechanism of clitoral engorgement and leads to diffuse clitoral cavernous fibrosis.68

Arteriosclerosis

In the rabbit, experimentally induced arteriosclerosis resulted in decreased pelvic nerve stimulation-induced vaginal blood flow and vaginal wall pressure.55

Conclusions

During sexual stimulation, the physiologic female sexual arousal response is elicited by sensory stimulation as well as central nervous system activation, resulting in increased genital blood flow and, to some extent, relaxation of genital smooth muscle structures. This culminates in a series of vasocongestive as well as neuromuscular events leading to physiologic changes, including engorgement of the labia, vaginal lubrication, and increased length and width of the clitoris, as well as increased sensitivity of the genitals, all representing the physiologic sexual arousal response in women. Modulation of vaginal and clitoral engorgement, vasocongestion, and vaginal lubrication may be antagonistically regulated by parasympathetic and sympathetic components of the autonomic nervous system of the female genitalia. Vasoactive intestinal polypeptide and nitric oxide may be the primary facilitators, and noradrenaline and neuropeptide Y the primary inhibitors, of the genital arousal response. There is still a need to expand our current understanding of the physiologic mechanisms responsible for the arousal response.

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