Women's Sexual Function and Dysfunction. Irwin Goldstein MD

Pathophysiologic mechanisms involved in genital arousal dysfunction

Noel N Kim, Abdulmaged M Traish

Introduction

Female sexual dysfunction consists of multiple disorders classified into the diagnostic categories of desire, arousal, orgasm, and pain (Fig. 6.2.1). Each of these categories involves both psychologic and physiologic aspects and requires subjective as well as objective assessments. However, this discussion will be limited to peripheral physiologic mechanisms that directly affect the genital organs and can be objectively assessed. In its most general terms, arousal disorder is defined as “the persistent or recurrent inability to attain or maintain sufficient sexual excitement that causes personal distress”.1 The normal female genital arousal response is manifested by engorgement and swelling of genital tissues and production of lubricating mucus and fluid transudate from the cervix, periurethral glands, and vagina (see Chapters 4.1—4.4, 5.1—5.6, and 6.1 of this volume). These physiologic events are dependent upon the structural integrity of the genital tissues and the function of neural, endocrine, and vascular systems that regulate and coordinate the genital arousal response. Women diagnosed with “sexual arousal disorder” may have sexual complaints of diminished vaginal lubrication, increased time for arousal, diminished vaginal and clitoral sensation, and difficulty with orgasm (see Chapter 9.4). These clinical conditions may exist, in part, due to disruptions in the normal vascular, neural, and/or endocrine/paracrine regulatory mechanisms with concomitant changes in genital tissue structure or cellular organization. It is reasonable to hypothesize that chronic disease states (e.g., hypertension, atherosclerosis, diabetes), physical trauma, endocrine imbalances, or medications that adversely affect genital blood flow or sensation contribute to genital arousal dysfunction. There is an increased awareness of the role of physiologic factors mediating female sexual arousal and a new appreciation for the role of organic pathophysiologic conditions resulting in female sexual arousal disorders. However, the cellular and molecular mechanisms responsible for disruptions in normal genital arousal remain unknown. Thus, building upon the previous sections of this textbook on genital tissue anatomy and physiology, this chapter focuses on established and postulated peripheral mechanisms within the genital tissues that may contribute to female genital arousal dysfunction (Fig. 6.2.2).

Vascular insufficiency

Vascular insufficiency states have been associated with disorders and diseases of the heart, brain, eye, and bladder, as well as arousal disorders in men.2-5 However, the association between vascular insufficiency and arousal disorders in women has been made only recently.6 Genital vasocongestion and vaginal lubrication responses result from increased blood flow to the clitoris, vagina, and labia. These hemodynamic processes are regulated by the tone of the vascular smooth muscle of the erectile tissue and blood vessels within the genital tissues. There is limited understanding of local regulatory mechanisms modulating clitoral, vaginal, and labial smooth muscle tone and how these mechanisms are altered by disease states. However, recent studies using animal models (see Chapter 5.6) of several different species indicate that the nitric oxide/cyclic guanosine monophosphate pathway is an important regulator of clitoral and vaginal blood flow.7-11

Figure 6.2.1. "Arousal disorder" is one of four main diagnostic categories of female sexual dysfunction and can be manifested in several different ways. Engorgement and lubrication of the genital tissues may be decreased or absent in women with arousal disorder.

A developing hypothesis is that diminished arterial inflow after sexual stimulation is a major factor contributing to impaired “genital arousal”, as manifested by inadequate genital engorgement. While animal models of disease that exhibit genital arousal dysfunction are generally lacking, several recently published studies provide insight into some potential pathophysiologic mechanisms. Laboratory studies that have demonstrated various conditions leading to vascular insufficiency and attenuated genital arousal are discussed in the following sections in the broader context of vascular disease. Relevant hypothesized mechanisms from the field of cardiovascular research are also discussed.

Atherosclerosis and fibrosis

In the female rabbit model, Park et al. induced atherosclerosis of the ilio-hypogastric-pudendal arterial bed by injuring the intima with a balloon catheter and maintaining the rabbits on a high- cholesterol diet for 16 weeks.12 When compared with control animals, rabbits with atherosclerotic lesions had significantly diminished vaginal and clitoral blood flow after pelvic nerve stimulation, as well as reduced development of pressure in vaginal and clitoral tissues.12 Upon histologic examination, clitoral and vaginal tissues from atherosclerotic animals exhibited diffuse fibrosis. In a separate study, clitoral corpus cavernosum tissue from atherosclerotic animals was found to have significantly decreased smooth muscle content with a concomitant increase in connective tissue.13

Figure 6.2.2. Specific molecular mechanisms responsible for genital arousal dysfunction remain unknown at present. Potential mechanisms of disease, derived from the study of other vascular systems, are presented.

While specific pathophysiologic processes have yet to be explicitly demonstrated in vaginal or clitoral tissues, it seems likely that the development of atherosclerotic plaques within the blood vessels feeding the genital tissues and the progression of disease would be similar to what has been described in the heart and coronary vessels. This process includes: (1) the accumulation of lipoprotein particles on the intimal surface; (2) entry of lipoprotein into the subendothelial space and subsequent modification (e.g., oxidation); (3) stimulation of inflammatory response by oxidized lipoproteins; (4) expression of adhesion molecules on the endothelial surface and attraction of monocytes via production of chemokines; (5) entry of monocytes into the blood vessel wall and differentiation into foam cells.14 In addition, the production of various cytokines and chemoattractants stimulates the proliferation of vascular smooth muscle cells and their movement into the intimal layer. Smooth muscle cells in both the medial and intimal layers synthesize greater amounts of extracellular matrix, contributing to the establishment of atherosclerotic lesions.

Atherosclerotic blood vessels that have developed significant stenosis may not maintain sufficient perfusion, such that female genital tissues are exposed to chronic ischemia and hypoxia. In penile cavernosal tissue, profibrotic mechanisms related to decreased perfusion and oxygenation have been pos- tulated.15 These mechanisms are based on the concept that tissue oxygen tension regulates the local production of vasoactive factors, growth factors, and cytokines that can modulate extracellular matrix metabolism. An important cytokine mediator of tissue fibrosis that is sensitive to changes in oxygen tension is transforming growth factor beta1. In tissue culture experiments, messenger RNA for transforming growth factor beta1 increased two- to three-fold when penile cavernosal smooth muscle cells were exposed to low oxygen tension (PO2 = 30mmHg) for 18-24 h.16 Similar studies in human penile cavernosal smooth muscle cells and rabbit penile cavernosal tissue have also demonstrated that prostanoid synthesis is suppressed at low oxygen tension and positively correlated with intracellular accumulation of cyclic adenosine monophos- phate.17-19 In separate studies, agents that increase intracellular cyclic adenosine monophosphate levels, such as prostaglandin E1 or forskolin, were shown to inhibit transforming growth factor beta1 and collagen synthesis in penile cavernosal smooth muscle.18,20

Thus, in vaginal and clitoral tissues, chronic hypoxia secondary to ischemia may induce transforming growth factor betaand inhibit the synthesis of prostaglandins, stimulating the accumulation of perivascular and interstitial collagen that is the hallmark of tissue fibrosis. It is also likely that other aspects of extracellular matrix metabolism are altered with ischemic hypoxia. These may include changes in the signaling or synthesis of trophic factors, such as connective tissue growth factor, vascular endothelial growth factor, fibroblast growth factor, insulin-like growth factor, platelet-derived growth factor, tumor necrosis factor alpha, endothelins, and interleukins, all of which have been linked to tissue fibrosis. Furthermore, matrix metalloproteinases are enzymes that break down fibrillar collagen while tissue inhibitors of matrix metalloproteinases are endogenous inhibitors of matrix metalloproteinases. Each of these two families of proteins can modulate signaling molecules, as well as actively regulate the rate at which collagen is deposited in or removed from the extracellular space. In addition, tissue inhibitors of matrix metalloproteinases and matrix metalloproteinases may themselves be induced or suppressed by different trophic factors. Thus, an imbalance in the normal types, amounts, or activity of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases can dramatically change the content of extracellular matrix within any given tissue. As the knowledge gained from the field of connective tissue research indicates, tissue fibrosis is a complex process that can involve numerous other biologic mediators. The specific mediators of female genital tissue fibrosis remain to be elucidated.

Endothelial dysfunction

The clitoral and labial erectile tissue and the vaginal lamina propria are all highly vascular structures that contain endothelial cells (see Chapter 5.4). The endothelium consists of a monolayer of cells that forms a single, continuous surface lining the vascular compartment throughout the body. The total mass of the endothelium has been estimated to be 500 g in the average adult human, the majority of which is contained in the pulmonary vasculature.21 Much like skin, the endothelium may be considered a single organ with multiple functions and differential responses that are dependent upon both the systemic and local environments. Among other functions, a healthy endothelium serves to provide an antithrombotic, antiinflammatory, and antiatherogenic surface while also regulating vascular tone and permeability. Diseased or damaged endothelium may be a major contributor to vascular insufficiency of female genital tissues. Endothelium-dependent relaxation of blood vessels has been shown to be compromised in animal models of atherosclerosis, hypertension, diabetes, aging, smoking, and renal failure.21-24 While it remains unclear whether endothelial dysfunction is a cause or a consequence of any of these disease states, its existence as a common pathologic state warrants consideration and further investigation.

The most commonly observed type of endothelial dysfunction is that of reduced endothelium-dependent relaxation of vascular smooth muscle. For the purposes of this discussion, this impairment is the most relevant. The endothelium produces many vasoactive compounds that can influence the contractile, trophic or synthetic function of vascular smooth muscle cells. Among the factors that cause relaxation are nitric oxide, endothelium-derived hyperpolarizing factor, prostacyclin, and endothelin (through endothelin B receptors). Among the factors that cause contraction are endoperoxides, thromboxane A2, superoxide anions, and endothelin (through endothelin A receptors). Dysfunctional endothelium may produce decreased amounts of relaxing factors and/or increased amounts of constricting factors. More specifically, attenuated endothelium- dependent relaxation may be caused by: (1) impaired signal transduction mechanisms within the endothelial cell; (2) changes in substrate availability for the production of specific vasoactive factors; (3) increased inactivation of relaxing factors; (4) impaired diffusion of substances to the smooth muscle; (5) increased release of constricting factors; and (6) decreased sensitivity of smooth muscle to vasoactive substances.23

Although many of the mechanisms listed in the previous paragraph have been demonstrated in animal models of disease, it should be stressed that conflicting data do exist and that some findings may depend on the specific vascular bed or tissue used for study. In rat retina, diabetic conditions resulted in down- regulation and structural modification of G-proteins.25 One of the more novel proposed mechanisms of dysfunctional endothelial signaling involves a decrease in the number of caveolae on the surface of endothelial cells. Caveolae are invaginated microdomains of plasma membrane that are rich in endothelial nitric oxide synthase and the family of transmembrane structural proteins known as caveolins, as well as cholesterol, sphin- golipids, and glycosylphosphatidylinositol-linked proteins. In addition, caveolae contain numerous other signaling proteins such as receptors with seven-transmembrane domains, G- proteins, adenylyl cyclase, phospholipase C, protein kinase C, calcium pumps, and calcium channels. Thus, these specialized signaling regions have been termed “transductosomes”.26 In rabbits that were maintained for 8 weeks on a hypercholes- terolemic diet, regions of aortic endothelium that were infiltrated by fatty streaks exhibited lower numbers of caveolae transductosomes, as well as decreased clustering density.26 These cellular changes were correlated with attenuated endothelium- dependent relaxation.

With regard to substrate availability and increased inactivation of relaxing factors, the well-studied example of nitric oxide will be used to illustrate such mechanisms. It is debatable whether significantly different plasma levels of L-arginine (a cosubstrate for nitric oxide synthase) occur in disease states. However, L-arginine supplementation has been shown to improve parameters of cardiovascular function, reduce myocardial ischemia, and lower systemic blood pressure and renal vascular resistance in various patient populations that smoked cigarettes or those that were diagnosed with coronary artery disease, hypertension, or hypercholesterolemia.27 In addition, accumulating evidence suggests that asymmetric dimethylargi- nine, an endogenous competitive inhibitor of nitric oxide synthase, plays an important role in endothelial dysfunction. Elevated levels of asymmetric dimethylarginine have been positively correlated with a variety of clinical conditions, including hypercholesterolemia, hypertriglyceridemia, hypertension, chronic renal failure, chronic heart failure, and diabetes mellitus type II.28,29 Alternatively, nitric oxide production may remain unchanged or even transiently increased in disease states, but there may also be increased inactivation. Particularly in diabetes, oxidative stress has been implicated as an important pathogenic mechanism. The addition of antioxidants and superoxide dismutase has been shown to improve endothelium-dependent relaxation in animal models of atherosclerosis and diabetes.23 Increased formation of free radicals and/or impairment in normal antioxidant mechanisms (e.g., superoxide dismutase, catalase, glutathione, ascorbic acid) can lead to accumulation of reactive oxygen species and superoxide anions that scavenge nitric oxide. The reaction between nitric oxide and superoxide may also progress to form peroxynitrite, which can modify key proteins, such as prostacyclin synthase and superoxide dismutase, and inactivate them.

While impaired diffusion of endothelium-derived relaxing factors and decreased sensitivity of vascular smooth muscle to these factors remain plausible mechanisms, far fewer studies have focused on these aspects and will not be discussed here, since they are not, in and of themselves, forms of endothelial dysfunction. The remaining mechanism of increased release of constricting factors by the endothelium has been reported in animal models of diabetes. Increased production of vasocon- stricting prostanoids has been observed in pial arterioles and aorta of diabetic rats.30-32 Evidence to support abnormally high production of nonprostanoid constricting factors, such as endothelins, remains inconclusive.

Thus, endothelial dysfunction can occur through various mechanisms, and it is likely that more than one mechanism is associated with a given disease state. Given the vascular nature of genital tissue and the importance of blood flow during the genital arousal response, perturbations in endothelial function are likely to be important mechanisms mediating genital arousal dysfunction.

Endocrine pathophysiology

There is growing evidence that alterations in the sex steroid hormonal milieu may, in part, contribute to sexual dysfunction (see Chapters 6.1 and 6.3). Imbalances in sex steroid hormones (estrogens, androgens, and progestins) may alter nerve function, synthesis or activity of growth factors, tissue composition and structure, and smooth muscle contractility. These changes may lead to decreases in genital blood flow and sensation. Since other chapters in this book address the physiology and pathophysiology of sex steroid hormones in greater detail, this section presents only a general hypothesized mechanism relating to genital arousal dysfunction.

Sex steroid hormones may regulate distinct cellular processes within the multiple layers and components of the vagina, clitoris, and labia. Each of these direct cellular interactions may influence specific processes such as growth and function of neurons, blood vessels, smooth muscle, endothelium, and epithelial cells. These changes may include alterations in: (1) the synthesis, secretion, and reuptake of neurotransmitters; (2) vascular and nonvascular smooth muscle contractility; (3) production of autocrine or paracrine vasoactive/trophic factors; (4) synthesis, deposition, and degradation of extracellular matrix components; and (5) mucification, keratinization, and/or permeability of vaginal epithelium. The additive, synergistic or antagonistic interactions of such cellular processes will ultimately determine the overall physiologic responses manifested as genital blood flow, vaginal lubrication, tissue compliance, or sensation.

Diabetes

Diabetes is known to cause multiple medical complications, affecting vascular, neural, and endocrine mechanisms (see Chapter 7.3). However, the effects of diabetes on sexual function in women have received limited attention in basic and clinical research.33-35 The most common sexual dysfunction in women with diabetes is decreased genital arousal with inadequate lubrication.33,36,37

Women with diabetes were also determined to have decreased sensation at both genital and extragenital sites.38 In addition, diabetic women may have decreased physiologic arousal responses to erotic stimuli when compared with nondiabetic women.39

In laboratory studies, vaginal tissue from diabetic rats exhibited attenuated contractile responses to exogenous norepinephrine as well as diminished relaxation to exogenous nitric oxide or calcitonin gene-related peptide.40 Further, both neurogenic contraction and relaxation responses elicited by electrical stimulation were inhibited in vaginal tissue from diabetic animals when compared with control responses. However, the mechanisms responsible for the observed changes remain unclear. In separate studies, vaginal tissues from diabetic rats were observed to have decreased epithelial thickness, decreased overall wall thickness, and atrophic submucosal vasculature.41 Moreover, the cross-sectional area of connective tissue and immunostaining for transforming growth factor beta1 was significantly higher in vaginal tissue from diabetic animals. Subsequent studies using female rabbits have indicated that the diabetic state inhibits both baseline and nerve-stimulated clitoral blood flow and causes diffuse clitoral cavernosal fibrosis.42 Recent investigations have measured the vaginal blood flow response to pelvic nerve stimulation in diabetic rats and have shown that vaginal blood flow is also significantly attenuated when compared with responses in control animals (A. Traish et al., unpublished observations; K. Park et al., personal communication).

Thus, the diabetic condition may cause a state of vascular insufficiency that leads to adverse changes in tissue structure. However, as the clinical findings suggest, there are most certainly other aspects that need to be explored. In general, diabetic complications are thought to arise from increased oxidative stress, which is associated with an array of hyperglycemia-induced alterations. These changes include protein kinase C activation, formation of advanced glycation end-products, and increased activity of the polyol and hexoseamine pathways.43 While the consequences of these individual pathways in various tissues have been extensively investigated, recent work suggests that enhanced superoxide generation within the mitochondria is the underlying mechanism that directly or indirectly stimulates these metabolic pathways. Nevertheless, the mechanisms by which diabetes modulates female genital arousal responses are not well understood and require further investigation.

Antidepressant medications

Antidepressants have long been associated with adverse effects on sexual function44-46 (see Chapter 16.2). However, the ability to draw conclusions from the data from most clinical studies has been limited for several reasons. First, the already high prevalence of sexual dysfunction in patients diagnosed with clinical depression makes it difficult to distinguish an increased prevalence or severity of sexual dysfunction due to treatment with antidepressants. Second, validated rating scales are often not used to assess sexual dysfunction. Moreover, the manner in which the prevalence of sexual dysfunction is determined (i.e., direct interview versus self-report) can affect the data collected. Sexual dysfunction in patients has been shown to be significantly lower by spontaneous reporting than with direct patient interview by physicians.44 Finally, many studies examining the relative effects of different antidepressants on sexual function are not done by direct comparison and lack placebo controls.

Angulo et al. have performed laboratory studies to investigate the effects of various antidepressants on vaginal and clitoral blood flow.47 In female rabbits, acute administration of venlafax- ine (5 mg/kg) and duloxetine (1 mg/kg), mixed inhibitors of serotonin and norepinephrine reuptake, significantly inhibited the increase in genital blood flow that is normally observed after pelvic nerve stimulation. The specific serotonin reuptake inhibitor paroxetine (5 mg/kg) also inhibited the genital blood flow response after pelvic nerve stimulation. Interestingly, serotonin itself or the highly selective inhibitor of serotonin reuptake escitalopram did not appreciably affect the genital blood flow response. Thus, it seems unlikely that the inhibitory effect on genital blood flow caused by venlafaxine, duloxetine, and paroxetine results from increased serotonin levels. In the same study, administration of L-arginine completely blocked the inhibitory effect of paroxetine on genital blood flow, while the alpha-adrenergic antagonist phentolamine prevented the inhibitory effect of venlafaxine. The inhibitory effect of duloxetine was partially attenuated by either L-arginine or phentolamine, and completely blocked by the combination of L-arginine and phentolamine. These data suggest that some serotonin reuptake inhibitors can also inhibit the production of nitric oxide in genital tissues and thereby attenuate genital blood flow, while others may increase the availability of norepinephrine in the genital vascular bed and cause vasoconstriction. While this initial study provides some insight, further elucidation of the mechanisms responsible for the inhibitory effects of antidepressants on sexual function is required. In addition to the roles of the nitric oxide, serotonin, and alpha-adrenergic signaling pathways, it also remains important to distinguish between the central and peripheral effects of various antidepressant drugs.

Figure 6.2.3. Hypothetic mechanisms of genital arousal dysfunction. Cardiovascular disease, deficient levels of sex steroid hormones, or medication (e.g., antidepressants) may all cause vascular insufficiency states of genital tissue, resulting in genital arousal dysfunction. Alternatively, vascular disease and/or sex steroid hormone deficiency may directly cause genital tissue atrophy and/or fibrosis. While many of the pathophysiologic states that are shown in the figure affect neuronal function, their associations with vascular mechanisms have been delineated much more clearly. It is likely that multiple mechanisms contribute to dysfunctional genital arousal.

Summary and conclusions

The physiology of genital arousal is highly dependent on the structural and functional integrity of the tissue, involving complex neurovascular processes modulated by numerous local neurotransmitters, vasoactive agents, sex steroid hormones, and growth factors. As discussed in this chapter, the vascular nature of genital tissue lends itself to many parallel comparisons from the already established field of cardiovascular biology (Fig. 6.2.3). However, it is also well known that different vascular beds can yield diverse responses to the same disease state. Thus, there are probably mechanisms that are unique to the genital tissues and their vasculature. For example, Д-5-androstenediol, a steroid hormone possessing both androgenic and estrogenic activity, binds to a unique nuclear receptor that may be preferentially expressed in the vagina.48,49 In addition, the alpha-adrenergic and purinergic signaling systems, the neurotransmitter vasoactive intestinal polypeptide, and the enzyme arginase have all been shown to regulate the genital arousal response. Whether any of these mediate genital arousal dysfunction remains to be seen. Thus, although there is much to learn about the normal physiologic mechanisms of genital arousal, additional understanding of the cellular and molecular mechanisms of pathogenesis will help to identify potential points of intervention for the treatment of female genital arousal dysfunction.

Acknowledgment

This work was supported by grants DK56846 (AMT) and DK02696 (NNK) from the National Institute of Diabetes and Digestive and Kidney Diseases.

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