Vulvovaginal Pain and Female Sexuality

Introduction

Women’s sexuality encompasses sexual identity, sexual function, and sexual relationships. It is modulated throughout life, by life and reproduction-related events, health, relationships, and sociocultural variables.1 The aging process, as well as disease and pain, are powerful contributors to female sexual dysfunction.

Addressing the sexual sequelae of chronic disease and its treatment is beginning to be accepted as a fundamental part of health care. Most of the sexual effects of any chronic disease are negative. Chronic illness impacts a woman’s sexual self-image, her energy and interest in sexual activity, as well as her ability to respond to sexual stimuli with pleasurable sensations, excitement, and orgasm. Pain and sexual dysfunction travel together. For example, in women, both migraine and tension-type headache are associated with sexual pain and hypoactive sexual desire.2 Chronic pelvic pain caused by endometriosis or other gynecological conditions leads to a significant reduction of quality of life and sexual satisfaction. Nevertheless, for many women with chronic illness and pain, sexuality remains extremely important. Despite fatigue and acquired sexual dysfunctions associated with chronic disease, sexual resilience can be substantial. Women with illness and pain may still treasure sexual intimacy.3

Vulvar pain disorders often yield devastating changes to sexual function. Most women who have genital syndromes that include sexual pain, with either genital touch, intromission (penetration), or vaginal discomfort with penile thrusting, will say that their pain disorder has had a major impact on their self esteem, sexual lives, and their relationships. Women with vulvar pain are known, however, to put up with great pain in order to continue sexual activity.4

Assessment and management of sexual dysfunction is therefore necessary in all women with chronic illness or pain of any etiology.

Normal female sexual physiology

Female genital sexual response consists of arousal-related changes of the vulvar and vaginal tissues often leading to orgasm. Orchestration of this complex process involves cognitive and psychological factors, neuroendocrine factors, central and peripheral neurophysiological pathways, vascular physiology, and sex steroid hormone regulation.

In the last few decades, more sophisticated technology than previously available has yielded substantial advances in the understanding of the physiological aspects of normal female sexual function and dysfunction, allowing less dependence on animal models. Technology, including neuro-imaging has been able to identify areas of the brain specific to arousal and orgasmic responses. Research on peripheral pathways and the interaction between central and peripheral mechanisms has provided a better understanding of female desire, arousal, and orgasm.5

The following is a brief description of central physiology as well as the physiology of peripheral arousal and orgasm. Anatomy and physiology of the vulva and vagina are described throughout the annotations.

Central physiology of women’s sexual function

The nervous system produces an array of cognitive, emotional, physical, and behavioral responses critical to sexual function. These are coordinated and controlled by the cerebral cortex, which interprets what sensations are to be perceived as sexual, and issues commands to the rest of the nervous system. Particularly important to function is the brain’s creation of sexual fantasies; recall of these may generate erotically stimulating sensations in women’s bodies.6

Mechanical stimulation of external genitalia by pressure or touch excites sensors within the skin, mucosa, and subcutaneous tissue. The excitation travels through the sensory nerves of the lower abdomen to the spinal cord, where it elicits both sympathetic and parasympathetic reflexes: blood flow to the genitals, glandular secretion, and smooth muscle contraction in sexual organs. The cerebral cortex and limbic system excite the hypothalamus, as well as other autonomic nervous system controls, so that spinal cord reflexes accompanying intercourse are even more stimulated in a self-propagating cycle.

Both the local and the central levels involved in sexual response depend on the neuroendocrine environment for integrity and sensitivity. Simultaneously, the barrage of sensory responses of the genitals in response to touch, as well as to the response of engorgement, travel up the spinal cord to the brain, sensory cortex, and limbic system eliciting the perception and reaction of pleasure.7

Physiology of peripheral arousal

Female genital sexual arousal is described as a combination of objective and subjective signs: the bodily reactions as vulvar swelling, vaginal lubrication, heavy breathing, and increased sensitivity of the genitalia, combined with the subjective experience of feeling pleasure and excitement.8

Increased blood flow to the genitals is the hallmark of sexual arousal. It results from sensory stimulation as well as central nervous activation during sexual stimulation. The increased blood flow culminates in a series of vasocongestive and neuromuscular events leading to physiological changes,9 all described below.

In vivo MR imaging of genitalia combined with gross and histologic examinations of cadaveric specimens have demonstrated six vascular compartments, comprising the external female genitalia, the clitoris, clitoral bulbs, labia minora, urethra, and vestibule/vagina.10 The clitoris and the clitoral bulbs represent erectile tissue with the greatest volume change with engorgement during sexual arousal compared with non-erectile tissues.11

External Genitalia in arousal

Labia

During sexual arousal, the blood flow to the labia is increased, leading to engorgement and lubrication. The size of the labia minora increases by as much as two to threefold,12 and their sensitivity to touch is augmented. Because the labia minora represent the entry way into the vagina, their lubrication (discussed below) is essential for penile penetration and thrusting without pain.13

Clitoris

In the unaroused state, the clitoral vasculature has a high sympathetically-mediated tone. The vessels are mainly closed,14 but demonstrate intermittent opening and closing, called vasomotion, 15 based on local tissue needs.

The nerve supply to the clitoris occurs through VIPergic nerves releasing vasoactive intestinal peptide (VIP) that dilates the arterial supply,16 and nitric oxide (NO), which promotes relaxation of the smooth muscle of the cavernous sinuses. 17 The two vasodilator neurotransmitters, combined with the central reduction of sympathetic tone, create increased blood flow to the clitoris as the trabecular smooth muscles relax and the intracavernous pressure rises.18 The body of the clitoris has a single layer of tough, fibrous tissue (tunica albuginea) between its connective tissue tunica and the erectile tissue (unlike the penis with a bilaminar structure), so that it becomes swollen or tumescent, but not rigid with true “erection” even when its vasculature is full.19

Internal Genitalia in arousal

Urethra

The female urethra, 4 cm in length, has walls containing blood-filled venous sinuses; triangular-shaped paracrine cells in the lining of the urethra are believed to have mechanoreceptor properties and to contain serotonin (5-hydroxytryptamine). Serotonin is known to power the sensitivity of nerve endings.20 Stretching of the urethra during coitus21 or during digital stimulation of the anterior wall may activate the mechanoreceptors to release serotonin, which sensitizes the nerve endings in the urethra, creating pleasurable sensations,22 and transforming the urinary structure into a sexual one.23

Vagina
Vaginal microcirculation

A number of different nerve fibers supply the vaginal capillary microcirculation; the exact functions of the various nerve fibers are not yet confirmed.24 It is known that multiple nerve related products influence vaginal microcirculation: adrenergic, cholinergic, and VIPergic nerve secretions, neuropeptide substance P (a sensory transmitter), neuropeptide Y (a vasonconstrictor), calcitonin gene-related peptide (a possible sensory transmitter and a peptide influencing capillary permeability ) and NO.25

Like other microcirculations, vaginal capillaries in the basal state are closed by contraction of the pre-capillary sphincters; the surface pO2 of the vagina wall is thus basally at a low, hypoxic level.26 When the local area around one of these capillaries becomes hypoxic, the released metabolites (pCO2, lactic acid,K+, adenosine triphosphate ATP) cause pre-capillary sphincter relaxation and the supplied capillaries to open up, washing away the metabolites and refreshing the local area with oxygen and nutrients. This intermittency of the microcirculation is known, as with the clitoris, as vasomotion.27 The degree of vaginal vasomotion is a sensitive and useful index of genital arousal in the research setting. Thus, during basal conditions, a high vasomotor tone of the arterial supply through central sympathetic activation and a high level of vasomotion keep the blood flow to the vagina at minimal levels.

At the beginning of sexual arousal, high sympathetic vasomotor tone and vasomotion minimize the blood supply to the vagina. Within seconds of acceptable or consensual sexual stimulus, there is reduction of central sympathetic tone and enhancement of the arterial supply through the action of released neuronal VIP and NO via the sacral anterior nerve root;28 as more opened capillaries are recruited, vasomotion decreases.29 As rapid recruitment of capillaries maximizes, the vagina becomes fully vasocongested (along with the labia and clitoris), and vasomotion disappears. The woman will subjectively perceive pelvic fullness and congestion, and reactive desire to dissipate the congestion with orgasm. Dissipation of congestion is very slow, even with orgasm that facilitates the action. A single orgasm does not usually cause complete dissipation.30 Orgasms, however, are the natural and pleasurable means to ameliorate the pelvic discomfort.

In addition, slow oscillations in vaginal blood flow have recently been documented, both in rats and humans, as a marker of sexual arousal.31 These oscillations appear independent of vaginal vasocongestion. The slow oscillations in vaginal blood flow have been correlated with subjective physiological arousal in healthy human volunteers, but display diminished responsiveness in women with female sexual arousal disorder (FSAD).32

Vagina: arousal and lubrication

In the sexually aroused vagina, capillary engorgement with blood leads to increased capillary hydrostatic pressure and transudation of plasma (ultrafiltrate) into the interstitial space around the blood vessels. The transudate fills up the interstitial space and exudes through and between the cells of vaginal epithelium to the surface wall of the vagina as vaginal lubrication. The final fluid is a modified plasma filtrate because the cells of the vagina can transfer Na+ ions vectorially from the lumen back into the blood33 and add K+ ions by secretion and cell shedding.34 Throughout the menstrual cycle, basal vaginal fluid has a higher K+ and a lower Na+ than plasma.35 In contrast, the arousal transudate has a much higher Na+ concentration than the basal fluid, approaching that of plasma.36 On cessation of sexual arousal, the vaginal Na+, together with osmotically drawn fluid, is transferred back into the blood, thus re-setting the vagina to the basal “just moist” condition.37

Vagina: anterior wall, possibly erotic structures

With the stimulation of deep pressure, the anterior vaginal wall is known to generate a more sexually pleasurable feeling than either of the lateral or posterior vaginal walls.38 The urethra, with its potential for providing pleasurable sensations, is located in the anterior vaginal wall. In addition, there is the controversial Grafenberg spot (G-Spot) a site on the anterior wall of the vagina that can also be stimulated by deep pressure to engorge, protrude into the vaginal lumen, and facilitate orgasm in women.39 Halban’s fascia represents a layer of fascia between the bladder and the anterior wall of the vagina that has been suggested to elicit highly pleasurable sensations leading to orgasm when adequately pressure-stimulated.40

Cervix and uterus in arousal

Although many studies have been done, the role of both the cervix and the uterus in sexual arousal has not been clearly defined.41 Uterine contractions are reported to occur during high levels of sexual excitement and at orgasm.42

Nipple and breast stimulation in arousal

Enhancement of sexual arousal by female nipple/breast stimulation has not been well studied. One recent study showed that the majority of the women in the sample demonstrated that stimulation of nipples/ breasts caused or enhanced their sexual arousal. 80 percent of the women agreed that when sexually aroused, stimulation of the nipples further increased their arousal.43

Peripheral physiology of orgasm

Orgasm is defined as a variable, transient, peak sensation of intense pleasure, creating an altered state of consciousness, usually accompanied by involuntary, rhythmic contractions of the pelvic striated circumvaginal musculature, with concomitant uterine and anal contractions, and myotonia that resolves the sexually induced vasocongestion (sometimes only partially), usually with an induction of well-being and contentment.44

Striated pelvic floor muscle changes during orgasm

Pelvic floor muscles are classified as superficial muscles (the urogenital diaphragm, including the ischiocavernosus, the bulbocavernosus, and the deep and transverse perineii) and the deep muscles, often described as the “pelvic diaphragm,” (ischiococcygeus and the levator ani).45 Annotation L The Pelvic Floor.

The pudendal nerve pathway with both afferent (sensory) fibers and efferent (motor) fibers is responsible for the generation of the rhythmic contractions of these muscles that occur in most women during orgasm. The number of the contractions varies with the duration and intensity of the orgasm.46

The purpose of these pelvic floor muscle contractions in women is not clearly established; suggested functions include female ejaculation, pleasure, restoration of vasocongested pelvic tissue to its basal state, and stimulation of the male.47

In the past, some experts have considered pelvic floor muscle contractions as an intrinsic and indispensable part of orgasm,48 49 while others have not.50 51 More recently, pelvic floor dysfunction has been linked to problems in sexual function.

In general, hypoactivity of the muscles (low tone) may lead to lack of pleasure during sexual intercourse and orgasm; in contrast, hyperactivity (high tone) may be part of the pathology linked to the sexual pain disorders.52 53

Clitoral stimulation in relation to orgasm

Clitoral stimulation is the main source of sensory input for eliciting orgasm.54 55 In female cats, the identified pathway shows that afferent (sensory) fibers from the clitoris travel exclusively in the pudendal nerve.56 While it is hypothesized that coital orgasm is triggered by stimulation of the internal genital organs–the vagina, cervix and uterus–the neurophysiologic support for the coital orgasm is less clear than the pudendal pathway for clitoral orgasm.57 Orgasm can be obtained by stimulation of the periurethral glans area, mons, breasts/nipples, by mental imagery or fantasy, or even by hypnotic suggestion. Orgasm is known to occur during sleep.58

Vagina in orgasm

The vagina is surrounded by the powerful pelvic striated musculature. It is innervated by VIPergic nerves that release a dilator of blood vessels, vasoactive intestinal peptide (VIP), and a relaxer of vaginal wall smooth muscles, nitric oxide (NO). At orgasm, the contractions of the striated pelvic floor muscles impinge on the vagina causing passive increases in its intraluminal pressure. No study has measured the vaginal smooth muscle and striated pelvic floor muscle at the same time during orgasm,59 making the contribution of muscle groups unclear.

Linking the degree of vaginal muscle contraction activity to the pleasure felt during the contraction activity has not been successful. While Masters and Johnson, reported that the stronger the orgasm, the greater was the number of contractions experienced, a study utilizing recordings of the intraluminal vaginal pressure during orgasm did not show any linkage between the orgasmic contractions and the intensity of pleasure.60

Uterus in orgasm

The function of contractile activity of the uterus at orgasm is also not understood. Besides Masters and Johnson’s work proposing that uterine contractions were expulsive and not involved in “up-sucking” material from the vagina, few measurements of this uterine activity during orgasm have been documented to date.61 62

Cervix in orgasm

A minimal amount of dilatation of the cervical os occurs immediately after orgasm, persisting for 20–30 minutes,63 allowing spermatozoal migration through the endocervical canal. Although the mechanism for this dilatation has not been studied, the cervix’s second highest concentration of VIP in the genital tract makes it possible that its relaxant action on the sparse smooth muscle present could be involved. 64

Rectal sphincter and pressure in orgasm

There is contraction of the rectal sphincter at orgasm, similar to the contractions of the vagina.65 Fluctuations in rectal pressure changes during orgasm have been studied with a spectrum analyzer that is capable of measuring the amplitude versus frequency of mechanical contraction. In roughly 90% of the orgasms induced in normal women by clitoral masturbation undertaken by their partners, alpha band (8–13 Hz) modifications may be identified.66

Human female sexual response

Masters and Johnson and Kaplan

Masters and Johnson defined a model of linear progression of normal human sexual response,67 starting with the excitement phase and moving successively to the plateau phase, the orgasmic phase, and the resolution phase. This model was later simplified by Kaplan68 to a three phase linear model of desire, arousal, and orgasm. These models assumed that women’s sexual response paralleled the male sexual response.

Rosemary Basson

Perhaps more useful now is Rosemary Basson’s concept of a non-linear sexual response cycle.

Figure 1: Human sex response cycle69

human_sex_response.fw

This model reflects the fact that no woman responds sexually the same way all the time; nor do all women respond the same way. The fluidity of normal sexual function, and the underlying complexity of women’s sexual experiences are depicted.

This representation is circular and depicts the phases of sexual response as overlapping and varying in order; it corresponds to data confirming that the majority of women in long-term relationships begin sexual experiences without (at that moment) sensing any sexual desire,70 although many women do. The model also correlates with the fact that there are common associations between disorders of desire, arousal, lubrication, and orgasm.71

In the human female sexual response cycle, depending on the situation, women can enter a sexual episode at any point. Simply wanting to feel emotional closeness to a partner allows many women to be open to sexual stimulation that then can lead to arousal. If this closeness does not occur during and after the sexual experience together, their motivation lessens. Many other factors motivate women to initiate or agree to sexual activity; over 235 distinct reasons have been identified.72 Verbal, auditory, visual, or physical sexual stimulation is required to move from this sexual neutrality; non-genital and genital non-penetrative stimuli are usually required.73 These stimuli themselves are important, but context and interpersonal and environmental factors are also crucial. Women are highly sensitive to environmental concerns such as privacy and fatigue at a late night hour, as well as concern about possible sexually transmitted diseases or undesired pregnancy. Other factors that interfere include biological issues of chronic fatigue, depression, pain, or medications. Psychological factors such as distractions, an inability to focus, fear of being sexually substandard, fear of a negative outcome such as pain, and fear of not being able to please her partner may play roles.74

In many cases, orgasm (represented by “emotional and physical satisfaction” in the model) is not essential to a woman’s feelings of pleasure and gratification, contrary to our goal-oriented culture’s expectation for orgasm with every sexual encounter. At times, women in long-term relationships initiate less and may play a more receptive role, where they feel desire and arousal after appropriate sexual stimuli occur.75 76 Conversely, women are known to be able to have intercourse or penetration without experiencing desire, arousal, or orgasm. They may not enter the circle at all. Cultural and religious expectations may impact sexual behavior.

Sexual dysfunction in the general population

In the general population, problems with sexual function are common. Two population-based surveys, using similar instruments, estimated that 33%77 and 35% 78 of women have experienced a problem with desire, arousal, orgasm, or pain. Finding help has been difficult because so little has been known about these problems and their causes. Recent research and technological advances, however, have expanded our understanding of women and their sexual difficulties. At the Third International Consultation on Sexual Medicine, in Paris in 2009, twenty-five committees of experts in male and female sexual medicine reviewed the last six years of advances in the field and included the following classifications for the area of female sexual dysfunction in their recommendations.

Classification of female sexual dysfunction79

1) Hypoactive sexual desire: There are absent or diminished feelings of sexual interest or desire, absent sexual thoughts or fantasies, and a lack of responsive desire. Motivations (here defined as reasons or incentives) for attempting to become sexually aroused are scarce or absent. The lack of interest is considered to be beyond the normative lessening with life cycle and relationship duration.

2) Female sexual arousal disorder: In the past, the definition of this disorder was: “persistent or recurrent inability to attain or maintain sufficient sexual excitement, which causes personal distress.” The recommendation of the expert committee from the 2009 Third International Consultation on Sexual Medicine broadened the definition considerably. This was based on the observation that women with arousal disorder have subjective lack of arousal despite normal genital vasocongestive response to sexual stimuli in the laboratory. The definition is broken down into four subtypes:

              a) Subjective arousal disorder: There is 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.

              b)  Genital sexual arousal disorder: There are complaints of 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 of the genitalia. Subjective sexual excitement still occurs from non-genital sexual stimuli.

              c) Combined genital and subjective arousal disorder: There is 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.)

              d) Persistent genital arousal disorder: There is spontaneous, intrusive, and unwanted genital arousal, e.g. tingling, throbbing, and pulsating in the absence of sexual interest and desire. Any awareness of subjective arousal is typically but not invariably unpleasant. The arousal is unrelieved by one or more orgasms and the feelings of arousal persist for hours or days. In 2021, an expert consensus opinion on this condition was agreed upon and published in the Journal of Sexual Medicine as, International Society for the Study of Women’s Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD).

3) Female orgasmic disorder: Despite the self-report of high sexual arousal or excitement, there is either lack of orgasm, markedly diminished intensity of orgasmic sensations, or marked delay of orgasm from any kind of stimulation.

4) Sexual pain disorders:

                a) Dyspareunia: Persistent or recurrent pain with attempted or complete vaginal entry or penile vaginal intercourse. The emphasis in this definition is on physical pain with attempted intromission.

                b) Vaginismus: There are persistent or recurrent difficulties for the woman to allow vaginal entry of a penis, a finger, or an object despite the woman’s expressed wish to do so. There is often (phobic) avoidance, involuntary pelvic muscle contraction, and anticipation/fear/experience of pain. Structural or other physical abnormalities must be ruled out/addressed. (Vaginismus)

                 c) Persistent Vulvar pain and Vulvodynia: The International Society for the Study of Vulvovaginal Disease (ISSVD) is comprised of gynecologists, dermatologists, pathologists, sex therapists, pelvic floor physical therapists, and others who treat or study women with vulvar pain syndromes. The vulvar pain classifications proposed by the ISSVD reflect a focus on the etiology of pain conditions which might lead to female sexual dysfunction. The first classification of 2003 has been replaced by the 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia.80

See Annotation K for an in-depth description of this information.

Sexual function with vulvar pain or vulvodynia

Figure 1 depicts the evidence-based conceptualization of women’s sexual responses in health. Figures 2 and 3 allow clinicians to understand the changes brought about by disease and pain.

Figure 2. Healthy adaptation of sexual response to chronic illness81

Healthy-adaptation-of-sexual-response-to-chronic-illness

This model illustrates changes in the sexual response cycle when a woman has a healthy adaptation to pain. Desire may be absent, but the woman’s reasons for having sex persist. Her illness may have increased her need for intimacy, but there may be less spontaneity and a need to plan sexual experiences. If her pain is well controlled and she is not depressed, she remains receptive to sexual stimulation that might arouse her. She may need a variety of changes in having intercourse: a different position, different stimuli, avoidance to touch in some areas, and other adjuncts.

Unfortunately, healthy adaptation may not occur, or her physical symptoms may predominate.

 

Figure 3. Sexual dysfunction resulting from chronic illness. 82

Sexual-dysfunction-resulting-from-chronic-illness

Figure 3 shows that the pain of chronic illness may push the partners apart. Lessened eroticism arising from the role of one partner as the caregiver also lessens the woman’s willingness to receive sexual stimulation. Stimulation may no longer be effective owing, in part, to the physical symptoms of the illness or psychological factors such as lowered self-image. Minimal arousal follows and no desire for more intense sexual stimulation is triggered. Eventually, the physical symptoms may be impacted by pain from dryness resulting from the lack of physiological congestion that comes from poor arousal. Figures 1-3 are equally relevant to understanding chronic vulvar pain or vulvodynia.

Impact of vulvovaginal pain on sexuality

Dyspareunia has been frequently conceptualized either as the direct result of physical and anatomical factors, or as a reflection of psychological/sexological difficulties. Whichever conceptualization one adheres to for the understanding of “sexual pain,” it is clear that both vaginismus and dyspareunia are frequently co-morbid with DSM-IV sexual dysfunctions.83 The role of psychosexual factors in contributing to the vulnerability of localized provoked vulvodynia is increasingly acknowledged.84 Essentially, the pain affects all phases of sexual function 85 with a global negative impact female sexual response in these women and a significant effect on their intimate relationships.

This order of functional impairment can be present either as a primary dyspareunia, or may develop as a secondary process arising after years of normal sexual functioning in a well-established, long-term relationship. In dealing with cases of sexual pain, health professionals may have to treat the entire spectrum of female sexual dysfunction, with each new impairment adding to the burden of the previous one.86 Most clinicians faced with a woman who is asking for help with these problems would be overwhelmed. In many cases, women do not ask for help.

More specific implications of pain and sexual dysfunction follow:

Pain and the brain: stress

The pain of vulvodynia probably results from more than one cause, or a combination of factors– all of which differ from woman to woman– and all best understood within the framework of what neuroscience has discovered: that there is a entire system of mind-brain-body interactions related to genetic and psychosocial risk factors, biological and/or infectious triggers, coping skills, and personality traits that affect how the brain perceives, processes and manages pain. None of these studies supports causality, but at times, the absence of identifiable physiologic pathology has led to the view that the pain may be solely due to psychological factors. This position may be as erroneous as emphasizing only the physiological aspects of the conditions.87

In response to stressors of the external and internal environment, the body produces hormonal and neurotransmitter mediators that turn on cellular and tissue responses throughout the body, and lead to coordination of physiological response to the circumstances at hand.88. Research has reinforced the fact that classic “fight or flight” stress mediators have protective as well as damaging effects. As researchers endeavor to discern which mediators protect and which damage, a new formulation addresses the relationship between challenges from the environment and biological response.

In place of the ambiguous term stress, two new concepts have been formulated. Allostasis represents the brain’s constant effort to process daily physical, environmental, social and psychological stressors and return the body to a steady state of balance or homeostasis. With allostasis, there is stability or homeostasis during changeAllostatic load refers to the wear and tear that the body experiences from repeated cycles of allostasis, as well as the inefficient ignition or shut down of these responses.89 When the body is unable to return to homeostasis, allostatic load (overload) manifests as loss of resilience and increased risk of disease. Fear, including social fear, is a significant trigger of the stress response90 and a source of allostatic load.91

Repeated exposure to stress either through early or chronic exposure causes wear and tear on the body’s ability to sustain balance and resilience. It is possible that stressful or traumatic life events in the past may “prime” the brain to contribute to the onset of pain. Adverse life events such as destructive relationships, parental divorce, or adverse childbirth experiences are more frequent in women with vulvodynia than in women without.92

In a population based study, women with vulvodynia were 2.6 times more likely to report lack of family support (comfort, encouragement and love). Women who developed vulvodynia as adults were significantly more likely to report childhood abuse, (physical or sexual) than age matched controls.93

The brain can actually be remodeled to be less efficient at restoring homeostasis. Demonstration that women with chronic vulvar pain have differences in their brain anatomy compared to age matched controls supports the concept of the brain as an important modulator of pain in women with vulvodynia. 94 In chronic pain patients, a tendency to focus on pain (attentional bias) increases pain, disability and distractibility.95

Altered levels of stress hormones and other neurotransmitters affect our thoughts, actions and emotions. 96 Catastrophizing refers to predicting negative outcomes and assuming that the negative outcome will be catastrophic. Catastrophizing is associated with depression and anxiety, two significant predictors of vestibular pain in postmenopausal women with painful intercourse. Estrogen levels were not predictive.97

The majority of women with provoked vulvar pain are highly stressed.9899 Stress is under consideration as an important etiologic factor in vulvar pain100 since, in the rodent, it actually alters the brain through microglial proliferation in the hippocampus and substantial nigra,101 the same areas that show increased gray matter density with provoked vulvodynia compared to controls.102 The gray matter density was related to the women’s clinical symptoms as measured by their pain thresholds at the introitus. Rosemary Basson’s models in Figures 1-3 depict the increased allostatic load resulting from the build-up from stress to pain sensitization, sexual dysfunction, and further stress.

Figure 4: Circular model of provoked vestibulodynia103

Figure-1-Basson

Figure 4: Circular model of provoked vestibulodynia to illustrate the compounding effects of subsequent sexual dysfunction on overall allostatic load: emotional distress associated with premorbid anxiety, depression, traits of catastrophization, harm avoidance, hyper-vigilance, self-dislike, perfectionism may be associated with neuroplastic changes in the central nervous system leading to central sensitization and pain amplification. Feelings of being sexually substandard compound the etiological factors and lessen sexual motivation and response. Pain-induced cognitive changes may impair processing of sexual stimuli generally and at the time of sexual activity.  Motivational changes associated with chronic pain circuitry may further impair sexual motivation. Stress responses of body and skin add to the skin pathophysiology.

Resilience describes a healthy body able to rebound from stress and disease. A number of attitudes and behaviors have been shown to strengthen the body’s ability to sustain or restore resilience and buffer against allostatic load. Acceptance, optimism, humor, cognitive flexibililty, religion/spirituality, altruism, social support, moderate physical activity/exercise are among them.104 These skills can be learned and are recognized as making a difference in people’s lives.105

Emerging research of two psychological therapies, Cognitive Behavioral Therapy (CBT) and mindfulness, suggests benefit to both pain and to sexual dysfunction.106 Control of pain to eliminate its negative reinforcement on sexual function is a logical first step.

Decreased libido

Decreased or absent libido is a common complaint in women of all ages who have vulvar pain conditions. In a study of cases and controls, women with vulvar vestibulitis (vulvodynia; see definitions in the ISSVD Terminology statement. Vestibulitis is an older term that may be used in some studies)107  reported lower levels of desire than the controls.108 In another case-controlled study, women with dyspareunia also reported diminished sexual desire. In a series of vulvar vestibulitis patients, 22.7% reported life-long low libido, 58.1% reported acquired low libido, and the remaining reported non-problematic sex drive.109 One other study of women with vulvar vestibulitis, however, reported that no differences were observed between the women and their partners on scores for desire.110

If desire is low, sexual activity becomes disappointing and more painful, creating a volatile emotional experience. Women do not experience pleasure and their bodies essentially shut down sexual desire. The longer the pain has been present, the higher the likelihood of a mutual disinterest in coital intimacy.111 Many women do not know that this is a normal response to pain.

It is also amazing to discover that women who have severe, disabling pain continue to attempt to have sexual intercourse in their wish to fulfill their partner’s needs and in attempts to maintain their relationship, despite obvious sensible advice not to have intercourse or sexual contact when they are having pain.112 113

While a lack of desire is not a life-threatening problem, it is often distressing and problematic in relationships.

Spectatoring

There is evidence that chronic sexual pain may lead to difficulties in information processing, including attentional mechanisms. Women with provoked vulvodynia have been found to have more catastrophic thoughts about painful intercourse and other issues, such as the negative consequences for their partners and the threat of the pain problem for the long-term durability of the relationship114 In experimental studies, increased attentional bias toward pain-related stimuli in tasks measuring implicit associations is found in women with provoked vulvodynia,115 suggesting hypervigilance for pain-related stimuli.116 On a self-report level, affective associations with sex cues are significantly more negative in women with provoked vulvodynia than in asymptomatic women.117

Masters and Johnson reported many years ago that it takes only a few episodes of painful intercourse before a woman’s focus changes from the pleasure of kissing and touching to anticipation of pain and failure.118 Worry and hypervigilance to pain begin. A concerned partner also starts to watch, anticipating her pain, as well. This process on the part of both the woman and her partner is called spectatoring. Spectatoring interferes with natural arousal and lubrication in the woman and may interfere with erectile function in a male partner. When couples have transformed their sexual interactions into this cognitive mode, they become divorced from the sensual orientation and focus of their sexuality and it is often difficult to return to easy sensuality.119 Indeed, in addition to treatment of the pain problem, therapy may include psychosexual and pharmacologic interventions for the woman to regain a serene and satisfying sexual intimacy.120

Problems with arousal

Despite a wish to be intimate, a woman with a background of pain and hypervigilance to pain finds that arousal becomes problematic. Women with provoked vestibulodynia (provoked vulvodynia) reported more frequent genital pain during sexual contact with their partners. They also reported more frequent problems and higher distress with lubrication, sexual arousal, and negative emotions during sexual activity with the partners.121 When the fear of pain is elicited during visual erotic stimulation, both women with and without provoked vestibulodynia responded with decreased genital arousal. When fear of pain was removed, even women with painful intercourse were able to become genitally sexually aroused to a similar degree as women without sexual complaints.122

Problems with orgasm

Women with dyspareunia and vaginismus have been shown to have less orgasmic capacity than controls, both during intercourse and with manual stimulation. In one study, women with provoked vestibulodynia (provoked vulvodynia) reported being less successful at achieving orgasm through oral stimulation, as well as through intercourse.123 In another study, pain also appeared to be a major factor, with 40.3% of women with provoked vestibulodynia (provoked vulvodynia) reporting orgasmic dysfunction.124

Learned response to pain (secondary vaginismus, pelvic floor dysfunction)

(Annotation D Patient tolerance for genital exam, Vaginismus).

Aversive behaviors and fear of interpersonal contact with a partner

Aversion is defined as persistent or recurrent phobic aversion to and avoidance of sexual contact with a sexual partner which causes personal distress.

If there is sexual pain and dyspareunia, and the process of spectatoring is maintained, over time, one or both partners may begin to develop sexually aversive behaviors. Expressions of affection are limited or absent. Women make a conscious effort to avoid activity that could lead to intercourse. It is not unusual to see couples where no physical contact is present secondary to fear of receiving or delivering pain. There may be less eye contact, physical teasing or affection, fewer hugs or passionate kisses. Physical avoidance may replace affectionate snuggling since affection may be misinterpreted as a sexual invitation.125

Women report distress over non-coital activity such as kissing or hugging their partners or even having an erotic dream or watching an erotic movie, since mild genital arousal (without any direct genital contact) may immediately elicit worsening of the pain.126 The woman fears pain and the partner fears hurting her; the two of them become frozen in their aversive tactics and avoidance of sex. A partner who is repeatedly sexually rejected or only reluctantly accepted feels hurt and frustrated and, finally, will often become angry or depressed. Over time, the sense of intimate connection with the partner is compromised.

Loss of libido or avoidance of intercourse in the male partner for fear of causing further pain to the female partner are common, but rarely addressed aspects of provoked vulvodynia.127 Men may develop sexual or genital symptoms such as erectile dysfunction.128

Guilt, lack of self-esteem, worries about relationship, poor couple bonding

With increasing dysfunction and the loss of intimate connection with the partner, the woman begins to feel guilty that she is not functioning well as a woman, wife, and partner, and becomes concerned about the impact on her marriage or relationship. Women commonly feel guilt about withholding sex and are afraid to speak out, continuing sexual activity until pain is unbearable.129 Sixty percent of women suffering from vulvar pain sought treatment for their pain, but 30% had to consult three or more physicians in order to obtain a diagnosis. The condition remained undiagnosed in 40% of the women who had seen a physician.130

With her effort to seek help, a woman is often informed that her pain is entirely psychological, further increasing her guilt and distress. Likewise, her partner may also be told the same thing: that this is psychogenic pain, everything is fine, and that she is just refusing to have intercourse. The partner may become increasingly unsupportive, adding to the strain on the relationship.

Although pain may precipitate many psychological manifestations, a primary psychological cause of vulvodynia is not supported.131 Evidence for a primary sexual disturbance has not been found.132

Nevertheless, the ongoing pain and resulting sexual impairment in study patients led to lower levels of desire, lower frequency of intercourse, higher levels of psychological distress, and lower levels of relationship adjustment than in controls.133

Anxiety and depression

Anxiety disorders, obsessive-compulsive disorder, social phobia, and depression are increased in women with vulvodynia.134 Higher depression scores predict higher pain ratings. Attempts to provide treatment are frequently unsuccessful if anxiety and depression are not adequately addressed, since untreated depressed patients report high rates of abnormal sexual function.135

In 215 case-controlled pairs of women with and without vulvodynia, all with no history of childhood abuse (physical or sexual), non-abused women with vulvodynia had more than 6-times the odds of mood disorders compared to non-abused women without vulvodynia.136

Co-morbid situations (increased pain leads to increased pain)

Sexual intercourse is associated with intense pleasure. The presence of pain is therefore in complete contrast to expectations, and evokes intense reactions in both the woman and her partner as they struggle to understand a condition that may take years to diagnose.137 They are constantly “trying” to see if the pain has dissipated, only to experience ongoing dyspareunia and disappointment. A multiplicity of hygiene and lifestyle changes, diets, topical treatments, herbal and prescription medications may yield no benefit.

Recent study of vulvar pain has led to observations of frequent association of vulvar pain with other pain syndromes:138 interstitial cystitis and painful bladder syndrome, endometriosis and pelvic pain, irritable bowel syndrome, fibromyalgia, pelvic obliquity, and lumbosacral disease. In addition to painful sexual relations, a woman may have one or more sources of pain elsewhere.

Continued painful intercourse induces more physical and emotional problems, leading to a downward spiral to the further dysfunction in the form of increased pain, fear, and pelvic floor muscle hypertonicity. The woman feels “broken” and her partner does not know how to “fix” her.

Healthcare challenges of treating sexual dysfunction and chronic vulvar pain

The presence of recurrent pain tends to elicit feelings of powerlessness in healthcare professionals139 for a number of reasons. The chronic nature of pain, and the strong emotions generated by the experience of pain in the patients are factors that challenge even the wisest clinician. The ability of genital pain to negatively impact the entire sexual response cycle and to generate other sexual dysfunctions that require treatment is highly complex. Little is known about the treatment of sexual pain.140 In addition, great diagnostic confusion exists regarding dyspareunia and vaginismus; few clinicians are comfortable with these diagnoses.141 Yet, recognition of the problems of pain and sexuality is present and the literature expands with empowerment for both patient and clinician.

Multi-disciplinary treatment approaches to sexual pain and dysfunction

1.) Identify and treat any known cause of vulvovaginal pain.

Completion of all of the steps of the algorithm is essential for diagnosis. The pelvic examination can be educational and therapeutic, as women learn about their bodies. Information and reassurance can be given after identifying a known cause of pain or recognizing that vulvodynia alone is the issue. (See table below). Treatment for each possible condition is included under the associated Annotation or Atlas text.

If no known cause can be ascertained, vulvodynia is a likely diagnosis.

Figure 5: Differential Diagnosis List for Vulvovaginal Pain and Irritative Symptoms with Associated Annotation Links

Candida vaginitis (P) Fistulas (O)
Desquamative inflammatory vaginitis(P) Dermatitis, dermatosis with ulcers, erosions, fissures, papules, pustules (H) (Atlas)
STIs: trichomonas (P), herpes (M) (Atlas), Chancroid (M) (Atlas) Systemic diseases, e.g., Crohn (Atlas) Sjögren, Behçet (B) (O)
Irritants and allergens (J)(H) (Atlas) Drug reaction (O)
Seminal plasma allergy (J) Vulvodynia, pudendal neuralgia (K)
Hypoestrogenization, inadequate lubrication (O) Psychosexual issues leading to poor sexual arousal, vaginismus (D)
Congenital anomalies (F), imperforate hymen (Q), vaginal septum (N)) Musculo-skeletal conditions (B)
Intraepithelial neoplasia (O) (Atlas) Pelvic floor dysfunction (L)
Squamous cell carcinoma (Atlas) Interstitial cystitis, painful bladder (L)
Regional pain syndromes (K)

2.) Treat the pain itself. (Annotation K)

Sexual function cannot be improved until the pain is in control. Even if one corrects the cause of some types of vulvovaginal pain, for example, herpes simplex infection, pain (e.g. post-herpetic neuralgia) may remain. Provide education and support about persistence of pain despite treatment of initiating cause.

3.) Identify pelvic floor dysfunction often present with pain.

Read the section on vaginismus.

Treat the pelvic floor. (Annotation L)

4.) Evaluate and arrange therapy for sexual dysfunction

Alleviating pain and pelvic floor dysfunction can make many problems disappear. However, other issues may interfere with resumption of sexual activity; fear of pain, with its associated aversions and closing of doors may persist, and sexual dysfunction may be independent of vulvovaginal pain. In addition, chronic anxiety and depression are co-morbid factors. Legitimizing and clarifying the women’s sexual concerns is therapeutic in itself, but the clinician identifying sexual dysfunction may need to refer the patient to a colleague for further pain management, for sexual therapy, or for management of her anxiety or depression.

There is little evidence to support many treatment modalities for women with sexual dysfunction. The following treatment modalities may be helpful.

  • Cognitive behavioral therapy: Cognitive behavioral therapy can assist the woman to work on maladaptive thoughts and change her often catastrophic self-view imposed by the illness. Sadly, some women view themselves as sexually substandard, feeling that they do not ‘deserve’ reasonable treatment in a relationship and will therefore even stay in abusive relationships (or choose no relationship at all). Other exaggerated or catastrophic thoughts that are amenable to cognitive therapy include: ‘sex is only for well women’, ‘no longer fertile, I am no longer sexually attractive’, as well as: ‘if intercourse is impossible, then no one will want me.’ Cognitive behavioral therapy is associated with improved sexual outcomes. 142
  • Psychoeducation: Psychoeducation provides information about general female sexual response and the personal situation of the woman. Through improved understanding of the causes and effects of the problem, psychoeducation can broaden a woman’s view of the issues with positive benefit. As the woman’s own sexual response cycle is outlined, it guides the therapy. The main features of psychoeducation include information about the condition, emotional support through groups, contacts, exchange of experiences with others suffering from the same condition, support, and promotion of medications, of psychotherapeutic treatments, and self-help techniques.
  • Mindfulness: Newer to Western medicine is the recent addition of the concept of mindfulness, which has been found to be an effective component of psychological treatments for numerous psychiatric and medical illnesses.143 Mindfulness is an Eastern practice with roots in Buddhist meditation, which focuses on the present moment and nonjudgmental awareness. It is helpful for reduced sexual sensations, distractions, and anxiety. In recent years, mindfulness has been incorporated into sex therapy and has been found effective for genital arousal disorder among women with acquired sexual complaints secondary to gynecologic cancer.144 Mindfulness-based psychoeducation (PED) has been shown to have a significant beneficial effect in a group format for women with sexual desire/interest disorder and/or sexual arousal disorders unrelated to cancer.145
  • Sex Therapy: Referral to a sex and/or couples therapist can bring significant benefit for women with sexual dysfunction. Couple’s counseling is helpful when there are conflicts in the relationship and/or sub-optimal communication. Sex therapists often are highly trained counselors, with special expertise in human sexuality. They may be physicians, psychologists, or social workers with additional training and experience. Certified sex therapists may be located through the website of the American Association of Sex Educators, Counselors, and Therapists: www.aasect.org. Their services may be covered by insurance. Sex therapy begins with education of women and men about the normal sexual response cycle. Cultural or religious concerns related to sexuality are managed. Sex therapy includes sensate focus exercises, whereby each partner is encouraged to take turns giving and receiving sensual, and later, sexual touches, caresses, and kisses. Initially, genital areas and breasts are off-limits. The idea of any goal or expectation is put aside for these ‘homework assignments.’ Usually, each session lasts 15–20 minutes and two, or preferably three, sessions should occur each week for 3–6 weeks. The couple, together with the clinician, decides when the breasts and genital areas are included. Ultimately, the act of intercourse (or vaginal penetration with a dildo) may be included. For some women with chronic disease or cancer, intercourse may not be possible and encouragement is given to expand the sexual menu for more erotic, varied, and exciting non-penetrative activities. Improved communication between couples is a goal of sex therapy, with help for the couple to negotiate a mutually acceptable frequency of sexual activity when varying levels of sexual interest exist and cause conflict. Stress, fatigue, and lack of privacy contribute significantly to low libido and sexual problems for women. A sex therapist may make suggestions regarding stress reduction, yoga, or other relaxation techniques. Couples are often encouraged to establish a regular “date” with time to focus exclusively on each other. A wide range of helpful resources exists, including books, audio-visual aids, and devices.
  • Psychodynamic therapy: When progress is not evident with standard approaches, women with marked anxiety and depression, post-traumatic stress disorder, prior physical, emotional, or sexual abuse, as well as other psychiatric disease, may benefit from referral for this in-depth form of psychotherapy. With psychodynamic therapy, the focus is on revealing the unconscious portions of a woman’s psyche that may be contributing to psychic tension and maladaptive behavior. This is a referral made only after thorough evaluation and familiarity with the woman and her problems and is not a primary approach for pain.

Pharmacologic therapies

Pain medications: Medication for vulvar pain is covered in Annotation K. Some of the medications used for pain are helpful with anxiety and depression, such as the tricyclic anti-depressants, and duloxetine. Anti-anxiety and anti-depressant medications are best managed with the help of a psycho-pharmacologist; since anxiety and depression worsen pain, this referral is an important consideration.

Estrogen: The majority of postmenopausal women will develop urogenital atrophy in the absence of estrogen therapy.146 Although evidence does not support a role for systemic postmenopausal hormone therapy in the treatment of sexual problems, if a woman with a previously satisfying sex life presents with sexual problems concurrent with the onset of hot flashes, night sweats, sleep disruption, and resulting fatigue, treatment of menopausal symptoms with systemic postmenopausal hormone therapy may lead to improvement in the sexual problem.147 Medical therapies include local or systemic estrogen for atrophy-related dyspareunia and reduced lubrication from a lack of estrogen as discussed in Annotation N.(LINK) Adequate local estrogen will alleviate burning and pain associated with estrogen lack but will not improve pain from other etiologies.

Androgens: Women in their late 30s and 40s have low androgen levels compared with younger women since testosterone levels in women decline gradually with age. Levels do not change abruptly with natural menopause. Data regarding androgen treatment of premenopausal women are limited and inconclusive.148 149 When considering androgen therapy in women of reproductive age, a clinician must recognize the significant potential risk of unplanned pregnancy and inadvertent exposure of a developing fetus to testosterone.

In postmenopausal women, the use of testosterone therapy is the most commonly studied androgen treatment for female sexual dysfunction. In most, but not all randomized trials, after the addition of testosterone to postmenopausal estrogen (with or without progestin) for women with natural or surgical menopause, there was improved sexual function.150 151 152 Testosterone is primarily used to treat issues with sexual desire or responsiveness, although all aspects of sexual function generally improve, including arousal and orgasmic response.153 One large controlled trial reports success in women who were not taking postmenopausal hormone therapy, (estrogen and/or progesterone).154 Testosterone will not be of value until pain is adequately addressed.

Testosterone is not, however, approved by the FDA for female use in the USA, although it is widely used in other countries. Clinicians prescribing it need to explain to their patients that it is, for this reason, still considered experimental.

A well absorbed and convenient form of testosterone is topical, compounded one percent testosterone cream (0.5 grams daily) applied to the skin of the arms, legs, or abdomen. There can be significant inconsistency in delivered dose of preparations from different pharmacies, or even between separate lots of product from the same pharmacy. Clinical trials have not evaluated the safety or efficacy of this compounded form of testosterone for any indication, including improvement of female sexual function. A number of other testosterone products exist but have significant limitations. Use of oral formulations is limited by the potential for adverse changes in lipids and liver function tests following first-pass hepatic metabolism.155 The oral product methyltestosterone in combination with estrogen (Estratest) was taken off the United States market in 2009. There are transdermal testosterone patches (e.g. Androderm™) and gels (e.g. Androgel™) formulated for men, but women should not be given these standard doses prescribed for men. If they are used, careful dose adjustment is required, as excessive testosterone levels will result. Cutting patches is not advised, as no data are available on product stability or resulting testosterone levels. A testosterone patch for postmenopausal women (Intrinsa 300 mcg) was used in many of the studies on efficacy and safety of testosterone. Currently it is available only in Europe. Testosterone injections and implants also exist but are not convenient. Their administration can be uncomfortable and high levels of the hormone have been problematic.

Side effects of testosterone

A paucity of data exists regarding adverse effects in women taking testosterone alone (without estrogen). The duration of studies is generally from three to 12 months so that the long-term safety of testosterone therapy is not known.

Topical administration of testosterone does not alter lipids. Serum high density lipoprotein cholesterol concentrations decline slightly in postmenopausal women receiving oral testosterone therapy. Overall cardiovascular risk related to the change in lipids is not known.

Testosterone and other androgens are aromatized (biochemically converted) to estrogens, making the risks of estrogen therapy possible with androgen treatment. A possible association between testosterone administration and breast cancer risk has been reported.156 Abnormal uterine bleeding has been reported in some women on testosterone, although there is no evidence of an increased risk of endometrial hyperplasia or cancer.157

Cosmetic side effects of testosterone, such as hirsutism and acne, are usually mild; irreversible virilizing changes (e.g. voice deepening, clitoromegaly) are rare and occur only with excessive dosing158

Monitoring for potential adverse effects in women on androgen therapy is necessary. Cosmetic changes such as acne and increased hair growth are usually detected by the patient. Given potential effects on lipids and liver function, normal values should be confirmed prior to initiating androgen therapy, reassessed approximately six months after starting treatment, and then annually thereafter.

A prudent safety precaution is the measurement of a free testosterone level or free androgen index (total testosterone/sex hormone binding globulin) in women using topical testosterone therapy. Holding the testosterone value within the normal range for reproductive aged women provided by the testing laboratory is the goal.

Testosterone levels have no value in determining the etiology of a sexual problem or in assessing efficacy of treatment, as several large, well-designed studies confirm the absence of a significant association between androgen levels and sexual function. The idea that low androgen levels are a primary factor in female sexual problems is based on the role of androgens in male sexuality and was promoted by the results of studies showing that supraphysiologic doses of exogenously administered androgens exerted a positive influence on some aspects of female sexuality.

Another androgen, dehydroepiandrosterone (DHEA), has been shown to improve sexual interest and satisfaction in some studies of women with the problem of adrenal insufficiency. It was not of value in perimenopausal or naturally postmenopausal women.159 DHEA has not been studied for treatment of sexual dysfunction in women with surgical menopause. Preliminary studies suggest a potential role for both intravaginal dehydroepiandrosterone and testosterone in the treatment of dyspareunia secondary to vulvovaginal atrophy. Confirmatory studies are required before either therapy can be recommended.160

Phosphodiesterase inhibitors: Phosphodiesterase (PDE-5) inhibitors such as sildenafil (Viagra) effectively treat male erectile dysfunction, but have had variable success in women. A randomized trial of nearly 800 pre- and post-menopausal women with disorders of desire, arousal, orgasm, and/or with dyspareunia, treated women with 10 to 100 mg sildenafil for 12 weeks. Sildenafil was no more effective than placebo in increasing the frequency of enjoyable sexual events or improving any aspect of sexual function.161 However, a randomized trial of sildenafil 50 or 100 mg for eight weeks was performed with women with major depression in remission and sexual dysfunction related to SSRI use. They had no history of prior sexual dysfunction. Compared to placebo, sildenafil significantly improved scores on the Clinical Global Impression sexual function scale, associated with improvement in orgasm function. The drug did not improve sexual desire and had no effect on hormone levels or indicators of depression.162

Addressing adverse sexual side effects from SSRIs

Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce libido in women and men, to cause anorgasmia in women, and to increase ejaculation latency in men. Of note, many other antidepressants including monoamine oxidase inhibitors (MAOIs), heterocyclic antidepressants, venlafaxine, and duloxetine have been associated with sexual side effects, although this phenomenon has been less well studied than with SSRIs.

Options for patients who complain of sexual dysfunction while on an SSRI include the following:

  • Dose reduction: Lowering the dose of the SSRI is sometimes successful, although not well studied. The antidepressant effect may diminish when the SSRI dose is decreased. This change needs to be discussed with the woman, and attempted cautiously with careful monitoring of the patient’s level of depressive symptoms.
  • SSRI switch: While there are reports of some SSRIs causing less sexual dysfunction than others, there are no definitive comparison studies.
  • Non-SSRI trial:  Bupropion, nefazodone, and mirtazapine appear to have no effect or only a limited effect on sexual function.
  • Addition of a second drug to offset the adverse effects: Sidenafil, as above, proved helpful in one study. While the addition of bupropion 150 mg/d added to an SSRI was no more effective than placebo in a controlled study,163 a controlled study of 150 mg bupropion twice daily showed improved sexual desire.164 A systematic review discussed a third randomized study which also demonstrated improvement in desire, though not orgasm, in women treated with an SSRI and bupropion 150 mg per day compared to SSRI plus placebo.165
  • Drug holidays: Drug holidays have not been well studied in patients with SSRI-induced sexual dysfunction. An open-label non-randomized study of weekend drug holidays found no benefit for patients taking fluoxetine and inconsistent results for patients taking sertraline and paroxetine.166

It is difficult to assess the relative benefits of all of these approaches, as clinical trial data are limited. Non-randomized studies must be interpreted with caution since many patients experience sexual dysfunction that is related to the depression itself, rather than the treatment.

When this is not possible, the patient is advised that at least part of the problem is the required medication, and adjustments can be suggested. The romantic context might be made more erotic, more intense sexual stimulation may be provided, and specific goals can be removed; for example, that intercourse or orgasm must necessarily occur.

References

  1. Graziottin A. Menopause and sexuality: key issues in premature menopause and beyond. Ann NY Acad Sci. 2010 Sep;1205:254-61
  2. Nappi RE, Terreno E, Tassorelli C, Sances G, Allena M, Guaschino E, Antonaci F, Albani F, Polatti F. Sexual function and distress in women treated for primary headaches in a tertiary university center. J Sex Med. 2012 Mar;9(3):761-9.
  3. Basson R. Sexual function of women with chronic illness and cancer. Womens Health (London, England) 2010; 6(3);407-29.
  4. Danielsson I, Sjoberg I, Wikman M. vulvar vestibulitis: medical, psychosexual, and psychosocial aspects, a case-control study. Acta Obstet Gynecol Scan 2000; 79:872-8.
  5. Salonia A. Giraldi A, Chivers M, et al; Physiology of Women’s Sexual Function: Basic Knowledge and New Findings. J Sex Med 2010 7(8): 2637-2660.
  6. Nappi RE, Ferdeghini F, Polatti F. Mechanisms involved in desire and arousal dysfunction. In:Goldstein I, Meston CM, Davis SR, Traish AM, eds. Women’s Sexual Function and Dysfunction. Study, Diagnosis and Treatment. London: Taylor & Francis; 2006: 169.
  7. Nappi RE, Ferdeghini F, Polatti F. Mechanisms involved in desire and arousal dysfunction. In:Goldstein I, Meston CM, Davis SR, Traish AM, eds. Women’s Sexual Function and Dysfunction. Study, Diagnosis and Treatment. London: Taylor & Francis; 2006: 169.
  8. Basson R, Leiblum S, Brotto L, Derogatis L, Fourcroy J, et al. Revised definitions of women’s sexual dysfunction. J Sex Med 2004; 1:40-8.
  9. Maravilla KR, Heiman JR, Garland PA, Cao Y, Carter WO, Peterson BT, Weisskoff RM. Dynamic MR imaging of the sexual arousal response in women. J Sex Marital Ther 2003;29(1 suppl):71–6.
  10. Yang CC, Cold CJ, Yilmaz U, Maravilla KR. Sexually responsive vascular tissue of the vulva. BJU Int 2006;97:766–72.
  11. Maravilla KR, Cao Y, Heiman JR, Yang C, Garland PA, Peterson BT, Carter WO. Noncontrast dynamic magnetic resonance imaging for quantitative assessment of female sexual arousal. J Urol 2005;173:162–6.
  12. Suh DD, Yang CC, Cao Y, Heiman JR, Garland PA, Maravilla KR. MRI of female genital and pelvic organs during sexual arousal. J Psychosom Obstet Gynaecol 2004;25:153–62
  13. Erdogru T, Savas M, Yilmaz N, Baykara M. Are normal hemodynamic responses invariably associated with normal penile rigidity and potency? Int J Impot Res 2001;13:10–3.
  14. Yilmaz U, Soylu A, Ozcan C, Caliskan O. Clitoral electromyography. J Urol 2002;167:616–20.
  15. Levin RJ. Sexual arousal—Its physiological roles in human reproduction. Annu Rev Sex Res 2005;16:154–89.
  16. Hauser-Kronberger C, Cheung A, Hacker GW, Graf AH, Dietze O, Frick J. Peptidergic innervation of the human clitoris. Peptides 1999;20:539–43.
  17. Creighton SM, Crouch NS, Foxwell NA, Cellek S. Functional evidence for nitrergic neurotransmission in a human clitoral corpus cavernosum: A case study. Int J Impot Res 2004;16:319–24.
  18. Yang CC, Cao YY, Guan QY, Heiman JR, Kuffel SW, Peterson BT, Maravilla KR. Influence of PDE5 inhibitor on MRI measurement of clitoral volume response in women with FSAD: A feasibility study of a potential technique for evaluating drug response. Int J Impot Res 2008;20:105–10.
  19. Maravilla KR, Cao Y, Heiman JR, et al. Serial MR imaging with MS-325 for evaluating female sexual arousal response: determination of intrasubject reproducibility. J Magn Reson Imaging 2003; 18:216-24.
  20. Levin RJ. The mechanisms of human female sexual arousal. Annu Rev Sex Res 1992;3:1–48.
  21. Riley A, Lees W, Riley E. An ultrasound study of human coitus. In: Bezemer W, Cohen-Kettenis P, Slobn K, van Son-Schoones, eds. Sex matters. Amsterdam: Excerpta Medica; 1992:29–32.
  22. Riley A, Lees W, Riley E. An ultrasound study of human coitus. In: Bezemer W, Cohen-Kettenis P, Slobn K, van Son-Schoones, eds. Sex matters. Amsterdam: Excerpta Medica; 1992:29–32.
  23. Levin RJ. The mechanisms of human female sexual arousal. Annu Rev Sex Res 1992;3:1–48.
  24. Hoyt R. Innervation of the vagina and vulva. In: Goldstein I, Meston C, Davis S, Traish A, eds. Women’s sexual function and dysfunction. 1st edition. London and New York: Taylor & Francis; 2006:113–24.
  25. Giuliano F, Allard J, Compagnie S, Alexandre L, Droupy S, Bernabe J. Vaginal physiological changes in a model of sexual arousal in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R140–R149.
  26. Wagner G, Levin R. Oxygen tension of the vaginal surface during sexual stimulation in the human. Fertil Steril 1978; 30:50–3.
  27. Levin RJ, Wylie K. Vaginal vasomotion—Its appearance, measurement, and usefulness in assessing the mechanisms of vasodilatation. J Sex Med 2008;5:377–86.
  28. Wagner G. Vaginal transudation. In: Beller F, Schumacher G, eds. The biology of the fluids in the female genital tract. Amsterdam: Elsevier North Holland, Inc; 1979:25–34.
  29. Levin RJ, Wylie K. Vaginal vasomotion—Its appearance, measurement, and usefulness in assessing the mechanisms of vasodilatation. J Sex Med 2008;5:377–86.
  30. Masters WH, Johnson VE. Human Sexual Response. Boston, Little, Brown, 1966.
  31. Allers KA, Richards N, Sultana S, Sudworth M, Dawkins T, Hawcock AB, Buchanon T, Casey JH, Wayman CI. Slow oscillations in vaginal blood flow: Alterations during sexual arousal in rodents and humans. J Sex Med 2010;7:1074– 87.
  32. Allers KA, Richards N, Scott L, Sweatman C, Cheung J, Reynolds D, Casey JH, Wayman C. II. Slow oscillations in vaginal blood flow: Regulation of vaginal blood flow patterns in rat by central and autonomic mechanisms. J Sex Med 2010; 7(3):1074-87.
  33. Levin RJ. Actions of spermicidal and virucidal agents on electrogenic ion transfer across human vaginal epithelium in vitro. Pharmacol Toxicol 1997;81:219–25.
  34. Wagner G, Levin RJ. Electrolytes in vaginal fluid during the menstrual cycle of coitally active and inactive women. J Reprod Fertil 1980;60:17–27.
  35. Wagner G, Levin RJ. Electrolytes in vaginal fluid during the menstrual cycle of coitally active and inactive women. J Reprod Fertil 1980;60:17–27.
  36. Wagner G, Levin RJ. Vaginal fluid. In: Hafez E, Evans T, eds. The human vagina. Amsterdam: Elsevier/North-Holland Biomedical Press; 1978:121–37.
  37. Levin RJ. The physiology of sexual function in women. Clin Obstet Gynaecol 1980;7:213–52.
  38. Salonia A. Giraldi A, Chivers M, et al; Physiology of Women’s Sexual Function: Basic Knowledge and New Findings. J Sex Med 2010 7(8): 2637-2660.
  39. Levin RJ. The G-spot—reality or illusion? Sex Relationship Ther 2003;18:117–9.
  40. Ladas A, Whipple B, Perry A. The G-spot—And other discoveries about human sexuality. New York: Henry Holt and Company; 1982.
  41. Levin RJ. The involvement of the human cervix in reproduction and sex. Sexual Relationship Ther 2005;20:251–60.
  42. Levin RJ. The mechanisms of human female sexual arousal. Annu Rev Sex Res 1992;3:1–48.
  43. Levin R, Meston C. Nipple/breast stimulation and sexual arousal in young men and women. J Sex Med 2006; 3:450-4.
  44. Meston CM, Hull E, Levin RJ, Sipski M. Disorders of orgasm in women. J Sex Med 2004; 1:66-8.
  45. van Houten T. Anatomy of the pelvic floor and pelvic organ support system. In: Goldstein I, Meston C, Davis SR, Traish A, eds. Women’s sexual function and dysfunction. Study, diagnosis and treatment. London: Taylor & Francis; 2006: 134–48.
  46. van Houten T. Anatomy of the pelvic floor and pelvic organ support system. In: Goldstein I, Meston C, Davis SR, Traish A, eds. Women’s sexual function and dysfunction. Study, diagnosis and treatment. London: Taylor & Francis; 2006: 134–48.
  47. Salonia A. Giraldi A, Chivers M, et al; Physiology of Women’s Sexual Function: Basic Knowledge and New Findings. J Sex Med 2010 7(8): 2637-2660.
  48. Masters W, Johnson B. Human Sexual Response, Boston, Little,Brown, 1966.s
  49. Levin RJ. The female orgasm—A current appraisal. J Psychosom Res 1981;25:119–33
  50. Kinsey AC, Pomeroy WB, Martin CE, Gebhard PH. Sexual behavior in the human female. Bloomington: Indiana University Press; 1953.
  51. Bohlen G, Held J, Sandersson M, Ahlgren A. The female orgasm: Pelvic contractions. Arch Sex Behav 1982;11:367–86.
  52. Graziottin A, Giraldi A. Anatomy and physiology of women’s sexual function. In: Porst H, Buvat J, eds. Standard practice in sexual medicine. 1st edition. Oxford: Blackwell Publishing; 2006:289–304.
  53. Graziottin A. Female sexual dysfunction. In: Bo K, Berghmans B, van Kampen M, Morkiek S, eds. Evidence based physiotherapy for the pelvic floor: Bridging the research and clinical practice. Oxford: Elsevier; 2005:266–77.
  54. Mah K, Binik YM. The nature of human orgasm: a critical review of major trends. Clin Psychol Rev 2001; 21:823-56.
  55. Darling CA, Davidson JK Sr, Jemmomgs DA. The female sexual response revisited: understanding the multiorgasmic experience in women. Arch Sex Behav 1991; 20:527-40.
  56. Giuliano F, Julia-Guilloteau V. Neurophysiology of female genital sexual response. In:Goldstein I, Meston CM, Davis SR, Traish AM, eds. Women’s Sexual Function and Dysfunction. Study, Diagnosis and Treatment. London: Taylor & Francis; 2006: 169.
  57. Giuliano F, Julia-Guilloteau V. Neurophysiology of female genital sexual response. In:Goldstein I, Meston CM, Davis SR, Traish AM, eds. Women’s Sexual Function and Dysfunction. Study, Diagnosis and Treatment. London: Taylor & Francis; 2006: 169.
  58. Levin R. The physiology and pathophysiology of the female orgasm. In: Goldstein I, Meston C, Davis S, Traish A, eds. Women’s Sexual Function and Dysfunction. New York, Taylor and Francis, 2006, 228-235.
  59. Salonia A. Giraldi A, Chivers M, et al; Physiology of Women’s Sexual Function: Basic Knowledge and New Findings. J Sex Med 2010 7(8): 2637-2660.
  60. Bohlen G, Held J, Sandersson M. Response of the circumvaginal musculature during masturbation. In: Graber B, ed. Circumvaginal musculature and sexual function. Basel: Kager; 1982:43–60.
  61. Levin RJ. Sexual arousal—Its physiological roles in human reproduction. Annu Rev Sex Res 2005;16:154–89.
  62. Fox CA, Wolff HS, Baker JA. Measurement of intra-vaginal and intra-uterine pressures during human coitus by radiotelemetry. J Reprod Fertil 1970;22:243–51.
  63. Masters W, Johnson B. Human Sexual Response, Boston, Little, Brown, 1966.
  64. Salonia A. Giraldi A, Chivers M, et al; Physiology of Women’s Sexual Function: Basic Knowledge and New Findings. J Sex Med 2010 7(8): 2637-2660.
  65. Levin RJ. The human sexual response- Similarities and differences in the anatomy and function of male and female genitalia. In: Janssen E, ed. The psychophysiology of sex. Bloomington:Indiana University Press, 2007:35-56.
  66. Van Netten JJ, Gorgiadis JR, Kortekaas R. 8-13 Hz fluctuations in rectal pressure are an objective marker of clitorally-induced orgasm in women. Arch Sex Behav 2008; 37:279-85.
  67. Masters W, Johnson B. Human Sexual Response, Boston, Little, Brown, 1966.
  68. Kaplan, HS. The New Sex Therapy. New York, Bruner/Mazell, 1974.
  69. Basson R. Sexual function of women with chronic illness and cancer. Women’s Health. 2010. 6(3), 407-429.
  70. Brotto L: The DSM diagnostic criteria for hypoactive sexual desire disorder in women. Arch. Sex. Behav. 39(2), 221–239 (2010).
  71. Brotto L: The DSM diagnostic criteria for hypoactive sexual desire disorder in women. Arch. Sex. Behav. 39(2), 221–239 (2010).
  72. Basson R, Leiblum S, Brotto L et al.: Definitions of women’s sexual dysfunction reconsidered: advocating expansion and revision. J. Psychosom. Obstet. Gynecol. 24, 221–229 (2003).
  73. Basson R. sexual function of women with chronic illness and cancer. Women’s Health 2010; 6(3):407-429.
  74. Basson R. sexual function of women with chronic illness and cancer. Women’s Health 2010; 6(3):407-429.
  75. Basson R. Female Sexual Response: the role of drugs in the management of sexual dysfunction. Obstetrics and Gynecology, 2001; 98:350-353.
  76. Clinical Fact Sheet: Female Sexual Response; Association of Reproductive Health Professionals, March 2008.
  77. Johnson SD, Phelps DL, Cottler LB. The association of sexual dysfunction and substance use among a community epidemiological sample. Arch Sex Behav 2004; 33:55-63.
  78. Klassen AD, Wilsnack SC. Sexual experience and drinking among women in a US national survey. Arch Sex Behav 1986; 15:363-92.
  79. Basson R, Wierman ME, van Lankveld J, Brotto L. Summary of the Recommendations on Sexual Dysfunction in Women. J Sex Med 2010; 7:314-326.
  80. Bornstein J, Goldstein A, Stockdale C, Bergeron S, , Pukall C, Zolnoun D, Coady D. 2015 ISSVD, ISSWSH and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. Obstet Gynecol 2016; 127(4):745-51
  81. Basson R. Sexual function of women with chronic illness and cancer. Women’s Health 2010; 6(3):407-429.
  82. Basson R. sexual function of women with chronic illness and cancer. Women’s Health 2010; 6(3):407-429.
  83. van Lankveld J, Granot M, Willbrord C, Schultz W, Binik Y, et al. Womens’s sexual pain disorders. J Sex Med 2010; 7:616-31.
  84. Brotto LA, Basson R, Gehring D. Psychological profiles among women with vulvar vestibulitis syndrome: A chart review. J Psychosom Obstet Gynecol 2003; 24:195-203.
  85. Bergeron S, Pukall C, Binik Y. Difficult cases: treatment of sexual pain disorders. In: Goldstein I, Meston C, Davis S, Traish A, eds. Women’s Sexual Function and Dysfunction. New York, Taylor and Francis, 2006, 529-535.
  86. Bergeron S, Pukall C, Binik Y. Difficult cases: treatment of sexual pain disorders. In: Goldstein I, Meston C, Davis S, Traish A, eds. Women’s Sexual Function and Dysfunction. New York, Taylor and Francis, 2006, 529-535.
  87. Jantos M. Vulvodynia: A psychophysiological profile based on electromyographic assessment. Appl Psychophysiol Biofeedback 2008; 33:29-38.
  88. McEwen B, Seeman T. Allostatic load and allostasis: Summary of the allostatic load working group. 2009: retrieved February 3, 2014 from http://www.macses.ucsf.edu/research/allostatic/allostatic.php
  89. McEwen BS, Stellar E. Stress and the individual: Mechanisms leading to disease. Arch Int Med 1993; 153:2093-2101
  90. Rodrigues SM, LeDouxJE, Sapolsky RM. The influences of stress hormones on fear circuitry. Ann Rev Neuroscience 2009; 32:289-313
  91. Ganzel BL, Morris PA, Wethingon E. Allostasis and the human brain: Integrating models of stress from the social and life sciences. Psychological Review 2010; 117(1):134-174
  92. Plante A, Kamm M A. Life events in patients with vulvodynia. BJOG:An International J of Obstet Gynaecol 2008; 115(4):509-14
  93. Harlow BL, Stewart EG. Adult-onset vulvodynia in relation to childhood violence victimization. Am J Epidemiol 2004; 161(9):871-80
  94. Schweinhardt P, Kuchinad A, Pukall CF, Bushnell MC. Increased gray matter density in young women with chronic vulvar pain. Pain 2008; 140(3):411-19
  95. Van Ryckeghem DM, Crombez G, Goubert L, Houwer JD, Onraedt T, Van Damme S. The predictive value of attentional bias towards pain-related information in chronic pain patients: A diary study. Pain 2013; 154:468-75
  96. Arnsten AF. Stress signaling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience 2009;10(6):410-22
  97. Kao A, Binik YM, Amsel R. Funaor D, Leroux N, Khalife S. Biopsychosocial predictors of postmenopausal dyspareunia: The role of steroid hormones, vulvovaginal atrophy, cognitivie-emotional factors and dyadic adjustment. J Sex Med 2012;9:2066-76
  98. Arnold L, Bachmann G, et al. Vulvodynia: Characteristics and associations with comorbidities and quality of life. Obstet Gynecol 2006; 107:617-24
  99. Khandker M, Brady S, Vitonis A, MacLehose R, Stewart EG, Harlow BL. The influence of depression and anxiety on risk of adult onset vulvodynia. J Womens Health 2011; 20:1445-51
  100. Tracy I, Bushnell MC. How neuroimaging studies have challenged us to rethink: Is chronic pain a disease? J Pain 2009; 10:1113-20
  101. Sugama S. Fujita M, et al. Stress induced morphological microglial activation in the rodent brain: Involvement of interleukin-18. Neuroscience 2007; 14:225-8
  102. Tracy I, Bushnell MC. How neuroimaging studies have challenged us to rethink: Is chronic pain a disease? J Pain 2009; 10:1113-20
  103. Basson R. The recurrent pain and sexual sequelae of provoked vestibulodynia: a perpetuating cycle. J Sex Med 2012;9:2077-92
  104. Feder A, Nestler EJ, Charney DS. Nature Reviews Neuroscience 2009; 10(6):446-57
  105. Cohn MA, Fredrickson BL. In search of durable positive psychology interventions: Predictors and consequences of long-term positive behavior change. J Postivie Psychology 2010; 5(5):355-66
  106. Basson R. The recurrent pain and sexual sequelae of provoked vestibulodynia: a perpetuating cycle. J Sex Med 2012;9:2077-92
  107. Bornstein J, Goldstein A, Stockdale C, Bergeron S, , Pukall C, Zolnoun D, Coady D. 2015 ISSVD, ISSWSH and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia. Obstet Gynecol 2016; 127(4):745-51
  108. Danielsson I, Sjoberg I, Wikman M. vulvar vestibulitis: medical, psychosexual, and psychosocial aspects, a case-control study. Acta Obstet Gynecol Scan 2000; 79:872-8.
  109. Graziottin A, Brotto LA. Vulvar vestibulitis syndrome: a clinical approach. J Sex Mar Ther 2004; 30:125-39.
  110. Van Lankveld J, Weijenborg P, Ter Kuile M. Psychologic profiles of and sexual function in women with vulvar vestibulitis and their partners. Obstet Gynecol 1996; 88:65-70.
  111. Graziottin A, Brotto LA. Vulvar vestibulitis syndrome: a clinical approach. J Sex Mar Ther 2004; 30:125-39.
  112. Van Lankveld J, Weijenborg P, Ter Kuile M. Psychologic profiles of and sexual function in women with vulvar vestibulitis and their partners. Obstet Gynecol 1996; 88:65-70.
  113. Danielsson I, Sjoberg I, Wikman M. vulvar vestibulitis: medical, psychosexual, and psychosocial aspects, a case-control study. Acta Obstet Gynecol Scan 2000; 79:872-8.
  114. Granot M. Lavee Y. Psychological factors associated with perception of experimental pain in vulvar vestibulitis syndrome. J Sex Marital Ther 2005; 31:285-302.
  115. Payne KA, Binik YM, Amsel R. Khalife S. When sex hurts, anxiety and fear orient attention towards pain. Eur J Pain 2005; 9:427-36.
  116. Van Lankveld JJ, Granot M, Schultz Weijmar, Binik YM, et al. Women’s sexual pain disorders. J Sex Med 2010; 7(1 Pt 2):615-31.
  117. Brauer M, ter Kuile MM, Janssen SA, Laan E. the effect of pain-related fear on sexual arousal in women with superficial dyspareunia. Eur J Pain 2007; 11:788-98.
  118. Masters W and Johnson V. Human Sexual Inadequacy, Boston, Little Brown, 1970.
  119. Masters W and Johnson V. Human Sexual Inadequacy, Boston, Little Brown, 1970.
  120. Graziottin A, Brotto LA. Vulvar vestibulitis syndrome: a clinical approach. J Sex Mar Ther 2004; 30:125-39.
  121. Van Lankveld J, Weijenborg P, Ter Kuile M. Psychologic profiles of and sexual function in women with vulvar vestibulitis and their partners. Obstet Gynecol 1996; 88:65-70.
  122. Brauer M, Laan E, ter Kuile MM. Sexual arousal in women with superficial dyspareunia. Arch Sex Behav 2006; 35:191-200.
  123. Meana M, Binik YM, Khalife S, Cohen D. Biopsychosocial profile of women with dyspareunia. Obstet Gynecol 1997; 90(4 pt 1):583-9.
  124. Graziottin A, Brotto LA. Vulvar vestibulitis syndrome: a clinical approach. J Sex Mar Ther 2004; 30:125-39.
  125. Leiblum SR, Treating Sexual Desire Disorders; a case book. Guildford Press, New York and London, 2010: p. 17.
  126. Graziottin A, Brotto LA. Vulvar vestibulitis syndrome: a clinical approach. J Sex Mar Ther 2004; 30:125-39.
  127. Graziottin A, Brotto LA. Vulvar vestibulitis syndrome: a clinical approach. J Sex Mar Ther 2004; 30:125-39.
  128. Dennerstein L, Lehert P, Burger H, Garamszegi C, Dudley E. Menopause and sexual functioning, 203-210.. In Studd J, ed. The Management of Menopause- the millennium review, New York, Parthenon Publishing, 2000
  129. Lynch PF, vulvodynia as a somatoform disorder. J Reprod Med 2008; 53:3390-6.
  130. Harlow BL, Wise LA, Stewart EG. Prevalence and predictors of lower genital tract discomfort. Am J Obstet Gynecol 2001; 185:545-50.
  131. Reed BD, et al. Psychosocial and sexual functioning in women with vulvodynia and chronic pelvic pain: a comparative evaluation. J Repro Med 2000;45(8):624-32.
  132. Danielsson I, Sjoberg I, Wikman M. Vulvar vestibulitis: medical, psychosexual, and psychosocial aspects, a case-control study. Acta Obstet Gynecol Scan 2000; 79:872-8.
  133. Meana M, Binik YM, Khalife S, Cohen D. Biopsychosocial profile of women with dyspareunia. Obstet Gynecol 1997; 90(4 pt 1):583-9.
  134. van Lankveld JJ, Grotjohann Y. Psychiatric comorbidity in heterosexual couples with sexual dysfunction assessed with the composite international diagnostic interview. Arch Sex Behav 2000; 29;479-98.
  135. Hensley PL, Nurnberg HG. Depression. In: Goldstein I, Meston CM, Davis SR, Traish AM. Women’s Sexual function and dysfunction, London, Taylor & Francis, 2006, 619.
  136. Khandker M, Brady SS, Stewart EG, Harlow BL. Childhood abuse, affect-based chronic stressors and the risk of adult onset vulvodynia. Psychosomatic Med 2012 (in press).
  137. Bergeron S, Binik YM, Khalife S, et al. A randomized comparison of group cognitive-behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar Psychovestibulitis. Pain 2001; 91:297-306.
  138. Arnold J, Bachmann G, Rosen R. et al. Vulvodynia: characteristics, and associations with comorbidities and quality of life. Obstet Gynecol 2006; 107:617-624.
  139. Bergeron S, Pukall C, Binik Y. Difficult cases: treatment of sexual pain disorders. In: Goldstein I, Meston C, Davis S, Traish A, eds. Women’s Sexual Function and Dysfunction. New York, Taylor and Francis, 2006, 529-535.
  140. Binik YM, Meana M, Berkley K et al. The sexual pain disorders: is the pain sexual or is the sex painful? Annu Rev Sex Res 1999; 10:210-35.
  141. Reissing ED, Binik YM, Khalife S, Cohen D, Amsel R. Vaginal Spasm, pain, and behavior: an empirical investigation of the diagnosis of vaginismus. Archive of Sexual Behav. 2004; 33(1): 5-17.
  142. Smith W,Beadle K, Shuster E. The impact of a group psychoeducational appointment on women with sexual dysfunction. Am J Obstet Gynecol 2008; 198(6):697.e1-697.e7.
  143. Brotto LA, Basson R, and Luria M. A mindfulness-based group psychoeducational intervention targeting sexual arousal disorder in women. J Sex Med 2008;5:1646–1659.
  144. Brotto LA, Heiman JR, Goff B, Greer B, et al. A Psychoeducational Intervention for Sexual Dysfunction in Women with Gynecologic Cancer. Arch Sex Behav (2008) 37:317- 329.
  145. Brotto LA, Basson R, and Luria M. A mindfulness-based group psychoeducational intervention targeting sexual arousal disorder in women. J Sex Med 2008;5:1646–1659.
  146. Gast MJ, Freedman MA, Vieweg AJ, et al. A randomized study of low-dose conjugated estrogens on sexual function and quality of life in postmenopausal women. Menopause 2009; 16:247.
  147. Shifren J. Sexual dysfunction in women: Management. In: UpToDate, Basow DS (Ed). UpToDate, Waltham, MA 2012.
  148. Davis S, Papalia MA, Norman RJ, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Ann Intern Med 2008; 148:569.
  149. Goldstat R, Briganti E, Tran J, et al. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause 2003; 10:390.
  150. Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri- and postmenopausal women. Cochrane Database Syst Rev 2005; CD004509
  151. Davis SR, van der Mooren MJ, van Lunsen RH, et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause 2006; 13:387.
  152. Shifren JL, Davis SR, Moreau M, et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study. Menopause 2006; 13:770.
  153. Shifren J. Sexual dysfunction in women: Management. In: UpToDate, Basow DS (Ed). UpToDate, Waltham, MA 2012.
  154. Davis SR, Moreau M, Kroll R, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008; 359:2005.
  155.  Hameed A, Brothwood T, Bouloux P. Delivery of testosterone replacement therapy. Curr Opin Investig Drugs 2003; 4:1213.
  156. Davis SR, Moreau M, Kroll R, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008; 359:2005.
  157. Allen NE, Key TJ, Dossus L, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer 2008; 15:485.
  158. Shifren J. Sexual dysfunction in women: Management. In: UpToDate, Basow DS (Ed). UpToDate, Waltham, MA 2012.
  159. Barnhart KT, Freeman E, Grisso JA, et al. The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J Clin Endocrinol Metab 1999; 84:3896.
  160. Nappi RE, Davis SR. The use of hormone therapy for the maintenance of urogynecological and sexual health post WHI. Climacteric. 2012 Jun;15(3):267-74
  161. Basson R, McInnes R, Smith MD, et al. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J Womens Health Gend Based Med 2002; 11:367.
  162. Nurnberg HG, Hensely PL, Heiman JR, et al. Sildenafil treatment of antidepressant-associated sexual dysfunction: a randomized controlled trial. JAMA 2008; 300(4); 395-404.
  163. Masand PS, Ashton AK, Gupta S, Frank B. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry.2001; 158:805.
  164. Clayton AH, Warnock JK, Kornstein SG, et al. A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 2004; 65:62.
  165. DeBattista C, Solvason HB, Poirier J, et al. A prospective trial of bupropion SR augmentation of partial and non-responders to serotonergic antidepressants. J Clin Psychopharmacol. 2003; 23:27
  166. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry. 1995; 152:1514.