Women's Sexual Function and Dysfunction. Irwin Goldstein MD

Mechanisms involved in desire and arousal dysfunction

Rossella E Nappi, Francesca Ferdeghini, Franco Polatti

Introduction

In the last few years, increasing knowledge has been achieved in the field of female sexual function from both a biologic and a psychosocial standpoint. However, despite the high prevalence of sexual complaints and problems in women (see Chapters 2.1—2.4 of this volume), our understanding of the pathophysiology of female sexual dysfunction is limited, mainly owing to methodological difficulties associated with the multidimensionality of the sexual response cycle. Animal models have been extremely helpful in understanding the neuroanatomic and neuroendocrine mechanisms that underlie sexual desire and arousal (see Chapters 5.1-5.6), but it is still very difficult to translate this growing body of basic research into the practical management of women with sexual symptoms. The inadequacy of our clinical approach is, indeed, confirmed by the paucity of available treatments specifically designed for female sexual dysfunction.1

This chapter will attempt to report the most relevant data currently available in order to understand the biologic mechanisms involved in desire and arousal dysfunction in women.

Libido and arousal

Physiologic sexual function (that is, briefly, an intact libido and the capacity to achieve satisfactory intercourse) is guaranteed by the integrity of (1) neural (autonomic, somatosensory, and somatomotor) and muscular substrates, (2) vascular supplies (arterial and venous), (3) hormonal environment, and (4) modulating mechanisms depending on cortical and hypothalamic-limbic structures. An impairment of both peripheral and central pathways involved in the sexual response cycle may lead to female sexual dysfunction, which includes disorders of libido, arousal and orgasm, and sexual pain2 (see Chapter 9.1).

Sexual desire or libido is the physical and mental need to behave sexually in order to experience a sense of reward. It may be activated by endogenous and/or exogenous stimuli, and it is very much a result of integrated biologic, psychosocial, and cultural factors. Multiple neuroendocrine messages are basically involved in promoting the instinctual component of libido (lust) modulated by emotional (attraction) and cognitive (attachment) aspects. A complex interplay among these factors gives rise to passion (see Chapter 3.3), affection, and commitment.3-5

The most recent definition of women’s sexual desire disorder, hypoactive sexual desire disorder, is “absent or diminished feelings of sexual interest or desire, absent sexual thoughts or fantasies and a lack of responsive desire. Motivations (reasons, incentives, etc.) for attempting to become sexually aroused are scarce or absent. The lack of interest is considered to be beyond a normative lessening with life cycle and relationship duration.”6

Such a definition introduces the concept of sexual arousal, a critical step in the woman’s sexual response cycle, which has been elegantly described as a mixture of subjective physical and mental feelings of sexual excitement and of objective awareness of genital sensations due to vulvovaginal engorgement and lubrication.6 Very briefly, it is most likely that women, by mentally feeling motivations to be sexually intimate, may activate desire and arousal or be responsive to sexual stimulation and become physically aware of peripheral genital tension and excitement. Thus, three subtypes of arousal disorders are described. The first includes subjective sexual arousal disorders defined as “absence of or markedly diminished feelings of sexual arousal (sexual excitement and sexual pleasure), from any type of sexual stimulation. Vaginal lubrication or other signs of physical response still occur.” The second subtype is genital sexual arousal disorder defined as “complaints of absent or impaired genital sexual arousal. Self-report may include minimal vulvar swelling or vaginal lubrication from any type of sexual stimulation and reduced sexual sensations from caressing genitalia. Subjective sexual excitement still occurs from nongenital sexual stimuli.” The third subtype includes combined genital and subjective sexual arousal disorder, defined as “absence of or markedly diminished feelings of sexual arousal (sexual excitement and sexual pleasure), from any type of sexual stimulation as well as complaints of absent or impaired genital sexual arousal (vulvar swelling, lubrication)” (see Chapter 9.1). Less common, but highly distressing, are the so-called persistent sexual arousal disorders. These are defined as “the spontaneous, intrusive and unwanted genital arousal (e.g. tingling, throbbing, pulsating) in the absence of sexual interest and desire”. There is also sexual aversion disorder, which indicates “the extreme anxiety and/or disgust at the anticipation of/or attempt to have any sexual activity”6 (see Chapter 16.9).

Libido and arousal are tightly connected but may also be independent. Both may be positive, nondysfunctional perceptions of pleasure and satisfaction. Both may be mentally and physically present when subjective and objective sexual responses follow the same track.

Key sexual organs for women’s libido and arousal

The brain

The nervous system produces a vast array of cognitive, emotional, physical, and behavioral responses that are critical to sexual function. The cerebral cortex is the coordinating and controlling center, interpreting what sensations are to be perceived as sexual and issuing appropriate commands to the rest of the nervous system. In particular, the brain creates sexual fantasies and by recalling them it may generate erotically stimulating sensations in women’s bodies. Mental awareness is important both to live out sexual experiences and to provide sexual satisfaction.

The mechanical stimulation of external genitalia by means of pressure, touch, and attrition provokes the excitation of sensorial receptors of several kinds, located in the skin, mucosa, and subcutaneous tissue. This excitation travels through the sensory nerves of the lower abdomen to the sacral spinal cord and triggers numerous autonomic reflexes (both sympathetic and parasympathetic). These reflexes control the selective afflux of blood to these regions, glandular secretion, and the contraction of smooth muscles in the sexual organs. The sensory cortex and limbic system, in addition to their signaling functions, excite the hypothalamus and other structures that control the autonomic nervous system. The result is that the spinal cord reflexes accompanying coitus are even more stimulated, creating a kind of self-perpetuating cycle. The neuroendocrine environment affects the integrity and the sensitivity of both the local and the central levels involved in the sexual response. At the same time, the mass of sensorial impulses emitted by the genitalia, in response to touch and to the local responses (i.e., genital engorgement), travel up the spinal cord to the brain, to the sensory cortex, and to the limbic system, where they elicit conscious perception and reactions of pleasure.

The main areas within the central nervous system modulating genital reflexes are brainstem structures (nucleus paragigantocellularis locus ceruleus and midbrain periaqueductal gray); hypothalamic structures (medial preoptic area, ventromedial nucleus and paraventricular nucleus); and forebrain structures (amygdala and hyppocampus)9 (see Chapters 5.1-5.3).

The genitals

The genitals play a critical role in the hemodynamic process of arousal, involving the peripheral neurovascular complex and the pelvic floor muscles. Arousal is modulated by sexual stimulation, hormonal milieu, and ascending/descending neurologic pathways. Thus, the genitals are directly responsible for the perception of objective activation in response to sexual stimuli, and their adequate functioning leads to orgasmic tension and sexual pleasure.10-15

The breasts

The breasts are one of the most predominate features of a woman and stand out as a symbol of womanliness and livelihood. They are relevant to sexual pleasure in both sexes, but erotic sensitivity varies enormously. Sex hormone changes affect the glandular composition; thus, the tenderness of the breasts may vary during the menstrual cycle, hormonal treatments, pregnancy, and menopause. During the sexual response, the breasts become engorged with blood, and a pink/red rush is common. The nipples are supplied with many nerve endings that make them highly sensitive to sexual stimulation, while thin muscle fibers enable them to become erect during arousal. The stimulation of the nipple and areola may lead directly to orgasm.16,17

The skin

The skin, the largest sexual organ, is woven with an intricate system of nerves that are responsive to changes in temperature, touch, and texture. Common areas identified as erogenous zones are very sensitive and responsive to stimulation, thus causing sexual arousal and pleasure. Erogenous zones include the neck, earlobes, mouth, lips, nipples, genitalia, buttocks, inner thighs, anus, backs of knees, fingers, and toes. However, erogenous zones are unique to each individual and virtually any part of the body can be erogenous, independent of the high concentration of nerves. The skin also represents an important part of a woman’s identity, being a symbol of beauty and sex appeal, and it is an important target for hormones that influence both the appearance and the threshold of sensitivity to external stimuli.16,18

Key sexual systems for women’s libido and arousal

The peripheral neurovascular complex

The precise location of autonomic neurovascular structures related to the uterus, cervix, and vagina is still a matter of debate. Uterine nerves arise from the inferior hypogastric plexus formed by the union of hypogastric nerves (sympathetic T10-L1) and the splanchnic fibers (parasympathetic S2-S4). This plexus, which has three portions: the vesical plexus, the rectal plexus, and the uterovaginal plexus (Frankenhauser’s ganglion), lies at the base of the broad ligament, dorsal to the uterine vessels, and lateral to the uterosacral and cardinal ligament. This plexus provides innervation via the cardinal ligament and uterosacral ligaments to the cervix, upper vagina, urethra, vestibular bulbs, and clitoris. At the cervix, sympathetic and parasympathetic nerves form the paracervical ganglia. The larger one is called the uterine cervical ganglion, and it is probably at this level that injury to the autonomic fibers of the vagina, labia, and cervix may occur during hysterectomy. The pudendal nerve (S2-S4) reaches the perineum through Alcock’s canal and provides sensory and motor innervation to the external genitalia. The arterial supply into the genitals comes from the internal and external pudendals, with extensive anastomoses, and follows the course of the nerves. Spinal cord reflex mechanisms produce sexual response at genital and nongenital level. The afferent reflex arm is primarily via the pudendal nerve. The efferent reflex arm consists of coordinated somatic and autonomic activity. One spinal sexual reflex is the bulbocavernosus reflex involving sacral cord segments S2-4 in which pudendal nerve stimulation results in pelvic floor muscle contraction. Another spinal sexual reflex involves vaginal and clitoral cavernosal autonomic nerve stimulation, resulting in clitoral, labial, and vaginal engorgement19 (see Chapters 4.1-4.3).

The pelvic floor muscles

Among the muscles forming the pelvic diaphragm, the levator ani muscle seems the most relevant to sexual function. It forms the floor of the pelvis and the roof of the perineum, and is divisible into three portions: the iliococcygeus, the pubococcygeus, and the puborectalis. The levator ani muscle fixes the vesical neck, anorectal junction, and vaginal fornices to the side wall of the pelvis by means of the suspensory sling and hiatal ligament. On contraction, it shares in the mechanism of evacuation (urination and defecation). During the sexual act, vaginal distention by the erect penis evokes the vaginolevator and

vaginopuborectalis reflexes, with a resulting levator ani muscle contraction. The levator ani muscle also contracts upon stimulation of the clitoris or cervix uteri, an action mediated through clitoromotor and cervicomotor reflexes. The levator ani muscle contraction leads to upper vagina ballooning, which acts as a receptacle for semen collection, to uterine elevation and straightening, and to elongation and narrowing of the vagina. These actions enhance the sexual response and facilitate reproductive function. The levator ani dysfunction is associated with parity, and it is more common in women with a history of a prolonged second stage of labor. Muscles of external genitalia, such as the bulbocavernosus (BC) and ischiocavernosus (IC) muscles, take an active part in the process leading to clitoral engorgement and vaginal lubrication2^22 (see Chapter 4.4).

Key sexual mediators for women’s libido and arousal

Sex steroids

Sex steroids exert both organizational and activational effects that are relevant to sexual function, and their actions are mediated by nongenomic as well as direct and indirect genomic pathways. Androgens are essential for the development of reproductive function and the growth and maintenance of secondary sex characteristics directly or throughout their conversion to estrogens. In addition, they are crucial to secure libido in both sexes. Estrogens also play a critical role in maintaining the physiologic function of many tissues, including the central nervous system and the genital apparatus, and of organs relevant to general health.23,24

The importance of adequate estrogen levels in preserving vaginal receptivity and preventing dyspareunia has long been established. Women with a level of estradiol of less than 50 pg/ml reported vaginal dryness, increased frequency and intensity of dyspareunia, pain with penetration and deep insertion, and burning. Women with higher estradiol levels had no complaints related to sexual desire, response, or satisfaction. Indeed, estradiol levels below 35 pg/ml are associated with reduced coital frequency, and decline in estradiol is related to a decline in sexual function.25,26

Data derived from in vivo animal models indicates that estrogen modulates genital blood flow, peripheral nerve function, vaginal tissue structural integrity, and, therefore, the process of lubrication.27 Within the nervous system, estradiol plays a permissive role in sexual receptivity by acting on its own estrogen receptor-alpha28 and by increasing the progesterone receptor expression that takes part in sexual response.29 In addition, estradiol stimulates oxytocin release and expression of its receptor,30 and facilitates the lordosis reflex by stimulating noradrenaline alpha-1 receptor.31 Some neurosteroids, such as allopregnanolone, a derivative of progesterone, are involved in the lordosis reflex at hypothalamic levels. Allopregnanolone may interfere with gamma-aminobutyric acid function, a major inhibitory neurotransmitter in the central nervous system.32 In addition, progesterone and its metabolites may indirectly influence sexual receptivity by modulating mood and cognition together with estrogens and androgens.33 The role of progesterone in peripheral vaginal arousal is poorly understood, even though the use of progestins seems to blunt the positive effect on vaginal dryness and dyspareunia exerted by estrogen, an action that seems highly dependent on biochemical properties of progestins.34

The most potent androgen, testosterone, is secreted by the adrenal zona fasciculata (25%) and the ovarian stroma (25%), while the remaining amount (50%) derives from peripheral conversion of circulating androstenedione. Plasma testosterone levels are in the range 0.2-0.7ng/ml (0.6-2.5 nmol/l), with significant fluctuations related to the phase of the menstrual cycle, being highest at ovulation, lowest during the early follicular phase, and higher during the luteal phase with respect to the early follicular phase. In addition, testosterone shows circadian variations, with a peak in the early morning hours. Testosterone is converted to dihydrotestosterone, but it can also be aromatizable to estradiol, in target tissues. Dihydrotestosterone is the principal ligand to androgen receptors. Other androgens in women include dehydroepiandrosterone sulfate, dehydroepiandrosterone, and androstenedione, which are considered to be proandrogens because they convert to testosterone.35

While estrogen decreases sharply at menopause, plasma testosterone levels fall slowly with age. At physiologic menopause, the cessation of follicular activity is characterized by a significant decline of ovarian production of androstene- dione, more than testosterone. The progressive fall of plasma testosterone concentrations is the consequence of the reduced peripheral conversion from its major precursor and from dehy- droepiandrosterone and dehydroepiandrosterone sulfate, which decline with age. Indeed, plasma testosterone and androstene- dione levels at 60 are about half those in women aged 40 years. As far as surgical menopause is concerned, bilateral oophorectomy, both premenopausally and postmenopausally, leads to a sudden 50% fall in circulating testosterone levels. Low androgens are associated with significant deterioration of sexual desire in premenopausal and postmenopausal women. There is, however, no consensus regarding the cutoff level for a normal range of testosterone because of the difficulties with sensitive assays of total and free testosterone in women and the fluctuations during the menstrual cycle and different ages.36,37

Testosterone, directly or through aromatization to estradiol within the central nervous system, contributes to initiation of sexual activity and permission for sexual behavior.38 A further nongenomic action by testosterone metabolites on sexual receptivity has been described at the hypothalamic level.39 Experimental data suggest that androgens directly modulate vaginal and clitoral physiology by influencing the muscular tone of erectile tissue and of vaginal walls. Androgens facilitate vaginal smooth muscle relaxation, especially in the proximal vagina, producing distinct physiologic responses in comparison with estradiol. In addition, testosterone being converted to estradiol, may enhance lubrication.40,41

Prolactin

Prolactin levels have been found to increase significantly after orgasm.42 An inhibitory action of prolactin on sexual desire and arousal has been demonstrated in hyperprolactinemic states and pharmacologic manipulations with psychoactive drugs.43 Such an effect is probably mediated by the interference with androgen biosynthesis and by the abnormal release of oxytocin. Amenorrhea and/or menstrual abnormalities, which are very common in hyperprolactinemic women, may contribute to an altered vaginal receptivity as a consequence of the hypoestro- genic state.

Oxytocin

Oxytocin has been strictly related to sexual behavior and may work synergistically with sex steroids to facilitate orgasm during sexual stimulation. The actions of oxytocin range from modulating neuroendocrine reflexes to establishing complex social and bonding behaviors related to the reproduction and care of offspring. The intensity of muscular contractions during orgasm in both men and women are highly correlated with oxytocin plasma levels.44 In addition, plasma oxytocin fluctuations throughout the menstrual cycle correlate with lubrication in fertile women with normal sexual activity, further supporting the role of this neurohormone in peripheral activation of sexual function.45

Endogenous opioids

Endogenous opioids and their receptors relate to a wide range of functions and behaviors, including the control of sexual behavior leading to intercourse, directly or through the modulation of several neurotransmitters and other neuropeptides. Opioids play an important role in female receptivity, but their involvement is quite complex, affecting differently anticipatory and contact components of sexual behavior.46

Classical neurotransmitters

The effects of several neurotransmitters on sexual function have been characterized within the central nervous systems by means of pharmacologic tools. Briefly, dopamine plays an excitatory role, promoting the craving for continued sexual activity once sexual stimulation has started, directly or though inhibiting prolactin release or stimulating oxytocin secretion. Even noradrenaline has a stimulating action on sexual behavior, while serotonin plays an inhibitory role on central desire and arousal by reducing the dopaminergic and noradrenergic activity.8,47 The function of the adrenergic/sympathetic and cholinergic/ parasympathetic systems in peripheral sexual function is still confusing and needs further investigation. Despite a rich cholinergic innervation to the vaginal arteries, acetylcholine plays a minor role in the regulation of the vaginal blood flow. Some data are in agreement with regard to the inhibitory effect of noradrenaline on the female sexual genital response. However, vaginal and clitoral smooth muscle contraction seems to be the result of activation of alpha-adrenergic receptors by noradrenaline released from adrenergic nerves. A facilitatory role of peripheral adrenergic activation on sexual arousal in women has been reported. The role of noradrenaline in the control of clitoral erection is indirectly supported by successful treatment of clitoral priapism by an alpha adrenergic agonist. Serotonin seems to exert a negative effect on sexual response by inhibiting the spinal sexual reflex at the periphery.48,49

Nonadrenergic, noncholinergic (NANC) neurotransmitters/neuromodulators

A great variety of nonadrenergic, noncholinergic neurotrans- mitters/neuromodulators have been identified in the female genital tract in animal models and humans, and are regulated by sex steroids. Nitric oxide synthase is present in the deep arteries, veins, and capillaries of the vagina and in nerve fibers within the glans and corpora cavernosa of the clitoris. Phosphodiesterase type 5 expression has been demonstrated in the clitoris and in the anterosuperior wall of the human vagina.50 After sexual stimulation, neurogenic and endothelial release of nitric oxide plays an important role in clitoral caver- nosal artery and helicine arteriolar smooth muscle relaxation. This leads to a rise in clitoral cavernosal artery inflow, an increase in clitoral intracavernosal pressure, and clitoral engorgement. The result is extrusion of the glans clitoris and enhanced sensitivity. Nitric oxide and vasoactive intestinal peptide are highly present and released in order to modulate vaginal vascular and nonvascular smooth muscle relaxation and to enhance vaginal blood flow, lubrication, and secretions. However, while the crucial role of the nitric oxide/cyclic guano- sine monophosphate system is strongly supported by increasing experimental evidence, no conclusive experimental data of functional involvement of vasoactive intestinal peptide has been forthcoming. Even neuropeptide Y has been identified in the human vagina and clitoris as having vasoconstrictive activity, along with calcitonin-gene related peptide, substance P, pituitary adenylate cyclase-activating peptides, and peptide histidine methionine, with unclear effects.13,51-53

To summarize the current conception of vaginal vasocon- gestion and increased lubrication during objective arousal, it is likely that vaginal arteriolar dilation from vasoactive intestinal peptide, nitric oxide and other unknown neurotransmitters, and neuropeptide Y-associated venoconstriction leads to increased interstitial fluid formation from vaginal submucosal capillaries. Neurogenic fluid filters through epithelial cells onto lumen with less potassium and more sodium than in the nonarousal state. Similarly, labia minora are able to release a transudate with the same modalities, while nitric oxide plays a dominant androgen- and estrogen-dependent role in vasocon- gestion of the clitoral cavernous bodies by regulating, together with prostaglandins, clitoral smooth muscle tone13 (see Chapter 5.4).

In clinical practice, the inadequate hormonal-dependent vaginal receptivity is the precipitating factor of dyspareunia that may cause other sexual symptoms and contribute to pain amplification during coital activity. It is extremely common to observe a lack of arousal and a decline of libido after a history of sexual pain; the consequent reduction of orgasmic capacity may reduce sexual satisfaction, negatively influencing sexual motivation, activity, and ultimately the couple’s relationship. This model explains the high degree of comorbidity of sexual symptoms in women, particularly throughout the climacteric period when hormonal imbalance is highly dominant.54

Conclusion

From this short summary of the biologic mechanisms involved in desire and arousal, it is fairly clear that every organic condition is able to impair the anatomic and physiologic substrates of a women’s sexual response cycle and may be a potential source of dysfunction. Endocrine, reproductive, urogenital, and surgical factors (see Chapter 16.7), as well as vascular, muscular, nervous, general health, drugs, lifestyle, and partner’s health and sexual function-related factors (see Chapters 8.1 and 8.2) should always be thoroughly investigated for appropriate management of women’s sexual dysfunctions.

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