Women's Sexual Desire and Arousal Disorders

CHAPTER 22 Committee 16 Women’s Sexual Desire and Arousal Disorders and Sexual Pain Chairman R. BASSON (CANADA) Vice-Chair W.C.M. WEIJMAR SHULTZ (THE NETHERLANDS) Members Y.M. BINIK (CANADA), L.A. BROTTO (USA), D.A. ESCHENBACH (USA), E. LAAN (THE NETHERLANDS), W.H. UTIAN (USA), U. WESSELMANN (USA), J. VAN LANKVELD (THE NETHERLANDS), G. WYATT (USA), L. WYATT (USA), S. LEIBLUM (USA), S.E. ALTHOF (USA), G. REDMOND (USA) 851 CONTENTS L. CONTEXTUAL NATURE OF WOMEN’S SEXUALITY AND DYSFUNCTION A. INTRODUCTION B. WOMEN’S SEXUAL DESIRE AND INTEREST : DISORDERS OF DESIRE AND INTEREST M. CHILD SEXUAL ABUSE AND SEXUAL DYSFUNCTION C. WOMEN’S SEXUAL AROUSAL AND AROUSAL DISORDERS N. FEMALE GENITAL MUTILATION AND SEXUAL DYSFUNCTION D. BIOLOGICAL BASIS OF AROUSAL AND DESIRE O. MANAGEMENT OF ANTIDEPRESSANT-ASSOCIATED SEXUAL DYSFUNCTION E. ASSESSMENT OF WOMEN’S SEXUAL DYSFUNCTION P. SEXUAL PAIN AND ITS MANAGEMENT F. PSYCHOLOGICAL ETIOLOGICAL FACTORS INVOLVED IN AROUSAL AND DESIRE DISORDERS Q. NEUROBIOLOGY OF THE PELVIS R. CHRONIC PAIN PHYSIOLOGY AND SEXUAL PAIN DISORDERS G. MANAGEMENT OF DESIRE AND COMORBID AROUSAL DISORDERS IN WOMEN S. CLINICAL PRESENTATION OF SEXUAL PAIN DISORDERS H. MANAGEMENT OF GENITAL AROUSAL DISORDER T. PSYCHOLOGICAL ASPECTS OF SEXUAL PAIN DISORDERS U. PELVIC FLOOR AND SEXUAL PAIN DISORDERS I. MANAGEMENT OF ORGASMIC DYSFUNCTION V. MUCOUS MEMBRANES AND SEXUAL PAIN DISORDERS J. THE ROLE OF ANDROGENS IN WOMEN’S SEXUAL FUNCTION AND DYSFUNCTION W. MANAGEMENT OF SEXUAL PAIN DISORDERS K. THE ROLE OF ESTROGEN IN WOMEN’S SEXUAL RESPONSE AND DYSFUNCTION X. CONCLUSIONS RE SEXUAL PAIN Y. CONCLUSIONS TO REPORT OF COMMITTEE 16 852 Women’s Sexual Desire and Arousal Disorders and Sexual Pain R. BASSON, W.C.M. WEIJMAR SHULTZ, Y.M. BINIK, L.A. BROTTO, D.A. ESCHENBACH, E. LAAN, W.H. UTIAN, U. WESSELMANN, J. VAN LANKVELD, G. WYATT, L. WYATT, S. LEIBLUM, S.E. ALTHOF, G. REDMOND psychological factors that may have influenced psychosexual development. Interestingly, despite medical factors, mood and psychological entities may more strongly correlate with sexual dysfunction. This has been shown to be true for women with diabetes [9], (level 3b) and women with gynecological surgery [10] (2b). It is possible women have variable proneness to sexual excitement and to sexual inhibition that is genetically and/or societally programmed. Early research is suggesting women have more proneness to sexual inhibition than do men [11]. This inhibition may be more about possible untoward consequences at sexual behaviour (including pregnancy) than about fear of sexual failure. Finally, dysfunction may be largely related to contextual factors - evidence of something psychologically or biologically amiss within the woman herself, being absent. Her sexual “dysfunction” is logical and adaptive [4, 11] It is nevertheless possibly highly distressing to her. It is therefore strongly recommended that in addition to considering which aspects of response are dysfunctional and causing distress, clinicians also routinely note the presence of associated factors: A. INTRODUCTION I. THE NATURE OF WOMEN’S SEXUAL DYSFUNCTION In countries and cultures where women are freely able to acknowledge their own sexual needs and sexual pleasure and expect freedom from pain with sexual activity, the prevalence of self-reported sexual difficulties (“disabilities”) as opposed to clinician's careful diagnosis, appears high, [1, 2] (level 4 evidence). Lack of interest in being sexual or sexual dysfunction - the term used when the expected physiological and/or psychological sexual response to sexual stimulation does not occur - may or may not be seen as a problem causing distress and reducing sexual satisfaction [3, 4]. Data suggest that of 33% of women in a nationally representative randomized study, who reported reduced sexual interest, 43% considered this to be a problem and of those, 87% reported sexual dissatisfaction [1]. When lubrication is absent or there is sexual pain, more (63% and 70%) find this a problem, causing sexual dissatisfaction in more than 80% of them. Another nationally representative community study confirmed more than 50% of women wanted professional help for the sexual problems self-disclosed in 41% of them [5]. - Predisposing factors in the woman's past affecting her psychosexual development, e.g. past abuse [12], (level 3b), - Precipitating and perpetuating factors in the current context which are disrupting to, and/or consequences of her sexual difficulties [4, 11, 12] (level 2b, 4) Dysfunction may be associated with medical disease, (level 3b evidence) e.g. neurological conditions affecting the autonomic nervous system [6], with pharmacological treatment, e.g. serotonergic antidepressants [7], with medical therapies, e.g. pelvic radiation, or with surgical procedures, e.g. radical hysterectomies for cancer of the cervix whereby damage to the autonomic nerves between the bladder and anterior vaginal wall is possible [8]. Dysfunction may also be associated with past or current - Past and present medical/surgical entities [6-8] (Level 3b). If phase(s) of the sex response cycle are the only major criteria governing the diagnosis of dysfunction, scientific proof of benefit of therapeutic intervention will be unlikely - put very simply, medication, for instance, will not ameliorate a problematic context. 853 Women’s Sexual Desire and Arousal Disorders and Sexual Pain R. BASSON, W.C.M. WEIJMAR SHULTZ, Y.M. BINIK, L.A. BROTTO, D.A. ESCHENBACH, E. LAAN, W.H. UTIAN, U. WESSELMANN, J. VAN LANKVELD, G. WYATT, L. WYATT, S. LEIBLUM, S.E. ALTHOF, psychological factors that may have influenced psychosexual development. Interestingly, despite medical factors, mood and psychological entities may more strongly correlate with sexual dysfunction. This has been shown to be true for women with diabetes [9], (level 3b) and women with gynecological surgery [10] (2b). It is possible women have variable proneness to sexual excitement and to sexual inhibition that is genetically and/or societally programmed. Early research is suggesting women have more proneness to sexual inhibition than do men [11]. This inhibition may be more about possible untoward consequences at sexual behaviour (including pregnancy) than about fear of sexual failure. Finally, dysfunction may be largely related to contextual factors - evidence of something psychologically or biologically amiss within the woman herself, being absent. Her sexual “dysfunction” is logical and adaptive [4, 11] It is nevertheless possibly highly distressing to her. It is therefore strongly recommended that in addition to considering which aspects of response are dysfunctional and causing distress, clinicians also routinely note the presence of associated factors: A. INTRODUCTION I. THE NATURE OF WOMEN’S SEXUAL DYSFUNCTION In countries and cultures where women are freely able to acknowledge their own sexual needs and sexual pleasure and expect freedom from pain with sexual activity, the prevalence of self-reported sexual difficulties (“disabilities”) as opposed to clinician's careful diagnosis, appears high, [1, 2] (level 4 evidence). Lack of interest in being sexual or sexual dysfunction - the term used when the expected physiological and/or psychological sexual response to sexual stimulation does not occur - may or may not be seen as a problem causing distress and reducing sexual satisfaction [3, 4]. Data suggest that of 33% of women in a nationally representative randomized study, who reported reduced sexual interest, 43% considered this to be a problem and of those, 87% reported sexual dissatisfaction [1]. When lubrication is absent or there is sexual pain, more (63% and 70%) find this a problem, causing sexual dissatisfaction in more than 80% of them. Another nationally representative community study confirmed more than 50% of women wanted professional help for the sexual problems self-disclosed in 41% of them [5]. - Predisposing factors in the woman's past affecting her psychosexual development, e.g. past abuse [12], (level 3b), - Precipitating and perpetuating factors in the current context which are disrupting to, and/or consequences of her sexual difficulties [4, 11, 12] (level 2b, 4) Dysfunction may be associated with medical disease, (level 3b evidence) e.g. neurological conditions affecting the autonomic nervous system [6], with pharmacological treatment, e.g. serotonergic antidepressants [7], with medical therapies, e.g. pelvic radiation, or with surgical procedures, e.g. radical hysterectomies for cancer of the cervix whereby damage to the autonomic nerves between the bladder and anterior vaginal wall is possible [8]. Dysfunction may also be associated with past or current - Past and present medical/surgical entities [6-8] (Level 3b). If phase(s) of the sex response cycle are the only major criteria governing the diagnosis of dysfunction, scientific proof of benefit of therapeutic intervention will be unlikely - put very simply, medication, for instance, will not ameliorate a problematic context. 853 rity are either biological or psychological. Rather, there is growing evidence of mechanisms by which the mind influences the various systems in the body - immunological, neurological and hormonal. We note the emerging fields of psychoneuroendocrinology and psychoneuroimmunology. Sexual function would appear to be a prime example of the mandatory blending of mind and body. A recent community study of 987 women in the United States provided data supporting the possibility that relationship disharmony may cause impaired sexual response rather than the opposite [4]. II. CATEGORIES OF WOMEN’S SEXUAL DYSFUNCTION Until recently, it has been accepted that women's sexual response is similar to men's such that women's sexual dysfunction mirrors categories of men's sexual dysfunction. This is not confirmed by empirical evidence - see Table 1. 1. TRADITIONAL CATEGORIES The traditional model of Masters, Johnson and Kaplan depicts a sexual desire phase and a subsequent phase of arousal characterized by genital congestion. A plateau of higher arousal continues the response on to an experience of high intensity arousal and orgasmic release, lasting some many seconds. A phase of resolution with physical and psychological well being completes the experience. This work was originally based on a subset of women who were willing to be monitored in great detail while they were sexually active in a laboratory and who were reliably orgasmic with intercourse. A phase of sexual desire initiating any sexual responding - such desire characterized by sexual thoughts and sexual fantasies, was later added by Kaplan given many women were voicing their sexual distress in terms of low sexual desire. The traditional categories of women's dysfunction have been based on this linear progression of discreet phases - desire, genitally focused arousal, plateau of arousal, orgasmic release and resolution. 3. ALTERNATIVE MODEL OF SEXUAL RESPONSE The following model (Figure 1) of women's sexual response attempts to reflect the features of women's sexual response itemized in Table 2. The model (on page 862) shows a woman's sexual response may begin for one of a number of reasons (incentives) [58]. At that stage, there may be no awareness of sexual desire. A willingness to be receptive to sexual stimuli in appropriate context allows her potential sexual arousal - both subjective excitement and physical responding. Many psychological and biological factors influence this information processing in her mind and determine her arousability. Once arousal is experienced, if it continues sufficiently long and is enjoyed, sexual desire may be accessed [58-60, 62]. This has been termed a responsive form of desire [15]. A psychologically and physically rewarding outcome need not necessarily involve orgasmic release(s). The wanting or motivation to be sexually active again is increased if the outcome is positive and decreased if it is either emotionally or physically dissatisfying. 2. EVIDENCE OF INACCURACIES OF TRADITIONAL MODEL OF HUMAN SEX RESPONSE AND SUBSEQUENT DEFINITIONS OF DYSFUNC- 4. INCORPORATION OF SPONTANEOUS OR TION INNATE DESIRE INTO MODEL The following evidence-based table lists facets of women's sexual function and dysfunction which contradict the traditional model of human sexual responding that underlies the existing definitions of women's sexual dysfunction. Sexual desire that appears to be “innate” or “spontaneous”, as reflected by sexual thinking/fantasizing/a wanting of sexual sensations per se, may or may not augment or override the cycle based on other motivations. See Figure 2. Women typically are far more aware of this type of desire early on in relationships. For some, it continues decades with the same partner, for the majority, it is infrequent [16-21]. Whether this apparent “innate” or “spontaneous” desire is truly so - is not able to be established. It has been argued that there is no such thing as spontaneous desire [63]. Based on motivation theory, motivation to engage in sex will be influenced by 1) an internal Both the International Statistical Classification of Disease and Related Health Problems (ICD-10) and the American Psychiatric Association Diagnostic and Statistical Manual (DSM-IVTR) assumes that it is possible to distinguish between organic and psychogenic etiology [56, 57]. However, not only is the precise etiology of women's sexual dysfunction frequently unclear, there is no evidence that the majo- 854 Table 1 : Facets of women’s sexual function and dysfunction which are at variance with traditional views of women’s sexual response Facets of Women’s Sexual Function/Dysfunction References LOE Cited An awareness of sexual desire is not the most frequent reason women accept or initiate sexual activity. 16, 17, 18, 19, 20, 21 2b, 3b, 4, 5 4, 22, 23 4 Sexual fantasies are often deliberate means to focus on the sexual stimulus rather than an indication of sexual desire. 16 4 The sexual, and the larger context is integral to women’s sexual function/dysfunction 4,24,25,26,27,28,29 30 2b, 4 The couple, rather than the woman, is the correct focus for assessing dysfunction. 4,24,29, 31-34 2b,4 The phases of women’s sexual response are not discreet and comorbidity of dysfunction is common. 29,31 34-171 1b, 2b, 3b, 4 Women’s experience of sexual arousal is not primarily to do with genital vasocongestion/ vaginal lubrication/perception of genital swelling. 4, 42-50 3b,4 Women’s subjective sexual arousal is strongly modulated by emotions and cognitions. 36,42, 51-54 2b, 3b, 4 42,53,54 3b, 4 55 4 Sexually healthy women in established relationships are frequently unaware of spontaneous sexual thoughts. There is no demonstrable lack of genital congestion in the majority of women (with or without arousal disorder), who watch erotic videos and disclaim any subjective arousal. The musculature of the vagina or around the vagina has not been shown to go into spasm. Table 2 : Evidence supporting an alternative model (figure 1) of women’s sexual response Facets of Women’s Sexual Function/Dysfunction References LOE Cited There are many reasons a woman initiates or agrees to sexual activity. 16,17,18,19,20,21 2b, 4 For one or more reasons, women choose to be receptive to sexual stimuli (or to provide them) and subsequently become sexually aroused. 16,17,18,19,20,21,22 2b, 4 Emotional intimacy with the partner is often a motivating force and influences her arousability to sexual stimuli. 4,17,20,21 2b, 4 Various psychological and biological factors influence the woman’s arousability, i.e. the processing of sexual stimuli in her mind potentially on to a state of subjective sexual arousal. 36, 42,51,52 2b, 3b, 4 58,59,60 5 Sexual desire and arousal continue together – each reinforcing the other. 58,59,60,61 5 A positive outcome, emotionally and physically, increases the woman’s motivation (reasons/incentives) to be sexual again in the future. 58,61 5 If the subjective sexual arousal is enjoyed, if the stimulation continues sufficiently long, and if she remains focused on the stimuli, then the arousal becomes more intense and an urge or “desire” for more of the sexual sensations is accessed. 855 Figure 1. Alternative model of woman’s sexual response. Copied with permission from Elsevier. Basson R. Obstet. Gynecol 2001; 98:350-3 Figure 2. blended sex response cycle showing many motivations to be sexual, spontaneous desire and responsive desire accessed during the experience. Copied with permission from Elsevier. Basson R. Obstet. Gynecol 2001; 98:350-3 856 state, disposition, or “sexual response system” ; 2) stimuli in the environment ; 3) rules for access or transgression that regulate the acting out of sexual tendencies. So, desire is part of arousal, triggered by a stimulus that has sexual meaning. It is facilitated or inhibited by situational and sexual partner variables. As such, sexual motivation will occur only when there are appropriate sexual stimuli present (given a sufficiently sensitive sexual response system). The occurrence of sexual motivation, including fantasies, must therefore be the result of sexual information processing of some kind, even though, in some or even most cases, it may not be clear what the initiating sexual stimulus was [63]. For most people, their sexual response system reacts with sexual stimuli in an automatic, unreflected and effortless way. This results in experiences that were not consciously intended, which may explain why so many people experience sexual desire “as if” it were spontaneous. b) ICD-10 : Loss of Sexual desire is the principal problem and is not secondary to other sexual difficulties, such as erectile failure or dyspareunia. c) Frigidity Hypoactive Sexual Desire Disorder [56]. 2. RECOMMENDED DEFINITION OF WOMEN'S SEXUAL INTEREST/DESIRE DISORDER ON (BASED EVIDENCE IN TABLES 1 AND 2) The word “interest” was chosen to cover the spectrum of motives/reasons underlying women's decision to agree to or instigate sexual activity. 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/incentives), for attempting to have sexual arousal are scarce or absent. The lack of interest is considered to be beyond the normative lessening with lifecycle and relationship duration [64]. Based on this alternative model of women's sexual response, revised and expanded definitions of dysfunction have been proposed by an international panel and will be described in this chapter [64]. B. WOMEN’S SEXUAL DESIRE AND INTEREST : DISORDERS OF DESIRE AND INTEREST II. PREVALENCE OF SELF-PERCEIVED LOW SEXUAL DESIRE/LOW SEXUAL INTEREST IN WOMEN Using the criteria of experiencing sexual desire only occasionally, rarely or never, the percentage of women affirming they have “low sexual desire” could be as high as almost 80% - only 22% of 1,335 women in a Scandinavian community study experienced sexual desire more than occasionally [1]. This percentage would drop to 14% in the same cohort of women if the criteria used for diagnosing low sexual desire is experiencing sexual desire only rarely or never.1 Some authors report on “low sexual interest” and others on “low sexual desire”. In the aforementioned study, women with reduced sexual interest amounted to 33% of the sample and almost half of those women perceived it to be a problem associated with sexual dissatisfaction. Previous randomized nationally representative surveys suggest from 8-33% of women self-report or are assessed to have via questionnaire +/- interview, low sexual interest or desire - see Table 3. Few studies ask about both desire and interest. Moreover, what the women interpret these words to mean, is often unclear. I. DEFINITIONS OF DISORDERED SEXUAL DESIRE AND INTEREST Given the broad range of awareness of “spontaneous” sexual desire (additional to desire experienced during sexual activity once sexual arousal has been accessed), across women [2, 16, 18, 22], it is quite unclear when any woman should be diagnosed with hypoactive sexual desire disorder. Moreover, given sexual desire is an uncommon reason women in established relationships give for having sex [1621] focusing on this aspect of sexual response is not clinically helpful. However this is the focus of exiting definitions. 1. CURRENT DEFINITIONS OF HSDD a) DSM-IV Definition : Persistent or recurrent deficiency (or absence) of sexual fantasies and desire for sexual activity. This disturbance causes marked distress or interpersonal difficulty [57]. Overall, age seems to have a fairly minimal effect on 857 Table 3 : Level 4 studies of more than 200 women in nationally representative samples giving prevalence of low sexual desire/interest Study Criterion Age Garde,1982 [23] Lacked or had no desire 40 21 Béjin,1982 [65] No or insufficient sexual desire 18-69 8 Kontula,1995 [66] Quite often were with decreased sexual interest 18-74 32 Hawton,1994 [67] Impaired sexual interest (only women with partners) 35-59 17 Ventegodt,1998 [68] Reduced sexual desire 38-88 17 Fisher,1999 [69] Sexual desire “often” lower than they would like it to be 18-45 39 Laumann,1999 [2] Lacking interest in sex 18-59 33 Fugl-Meyer,1999 [1] Sexual desire never or rarely 18-74 14 Fugl-Meyer,1999 [1] Decreased sexual interest 18-74 34 the concern of low sexual interest or the concern of low sexual desire. However, two studies [1, 66] show increasing prevalence of low desire after the early 50s. In contrast, other studies show a marked [68] or mild [2] decrease with age. Modest increase with age but less distress about it, characterizes other studies [4, 67]. Complicating all of this is the lessening of desire with relationship duration [21]. Prevalence in % which suggest otherwise. In view of the evidence to date, acceptance of the aforementioned revised definition of low sexual interest is strongly advocated. The innate or spontaneous component of sexual desire may be in part hormonally based [70], specifically related to androgen levels and sensitivity of the androgen receptor. It is also known to relate to relationship duration [1, 21, 71] and to life cycle with reports suggesting lower levels in the 25 to 34-yearold women (as compared to those immediately younger and older) and in women over 49 years of age [1, 66, 72]. III. THE PARADOX OF THE CRUCIAL ROLE OF SEXUAL AROUSAL AND THE HIGH PREVALENCE OF COMPLAINTS RE LOW DESIRE COMPARED TO COMPLAINTS RE LOW AROUSAL C. WOMEN’S SEXUAL AROUSAL AND AROUSAL DISORDERS The crucial role of sexual arousal is apparent from the alternative models, Figures 1 and 2. However, complaints of low interest or low desire far outnumber arousal complaints. Careful history-taking from women complaining of low sexual desire frequently identifies a difficulty with becoming aroused. Women find it hard to separate the two problems. The comorbidity of arousal and desire disorder is well documented [31, 35, 36, 38, 39]. It is recommended that women able to be aroused and have rewarding experiences but lacking apparently “spontaneous” sexual thinking and fantasizing be considered to be sexually healthy given the wide variability across women of this latter aspect of their sexuality. This is in contrast to the existing definitions of hypoactive sexual desire disorder I. COMPLEXITIES OF SEXUAL AROUSAL The past focus on just one aspect of women's sexual arousal, namely, genital vasocongestion, specifically the increase in lubrication fluid resulting at least in part from that increase in vasocongestion, has led to misunderstanding of women's complaints of low sexual arousal [73]. In the clinical setting, if the difficulty is absent lubrication, the woman will typically complain of vaginal dryness or discomfort with intercourse. In contrast, when she speaks in terms of absent sexual arousal, she is referring to subjective 858 gasmic women, and a control group of 12 women [46]. Similarly, Morokoff and Heiman [42] failed to find differences in VPA between 11 women with sexual arousal disorders who presented for sex therapy, and a control group of 11 women. Twenty-nine medically healthy women with sexual arousal disorder (15 premenopausal ; 14 postmenopausal), diagnosed according to DSM-IV criteria, showed no evidence of impaired genital congestion [54]. These women responded with an increase in vaginal vasocongestion to visual sexual stimuli, an increase that did not deviate from that of 30 age- and menopausal status-matched women without sexual problems. In addition, these women's VPA response did not occur at a slower rate. The women with sexual arousal disorder were carefully diagnosed, using strict and unambiguous criteria of lack of awareness of genital responsiveness, and in a similarly careful way it was established that the other women did not have any sexual dysfunction. It seems plausible that with respect to sexual function, these groups were more homogeneous, and differences between groups were greater, than was the case in the three studies mentioned above. Despite that, this study again failed to find differences in vaginal vasocongestion between women with and without sexual arousal disorder. Thus women's complaints of lack of genital responding may be conceptualized at least in part as an inattention to, or disconnection from physiologically healthy vasocongestion. sexual excitement in her mind [53]. When she speaks of overall sexual satisfaction or sexual distress, data suggests impaired vaginal lubrication to be a nonsignificant predictor [4]. Even recently developed questionnaires may not contain questions regarding subjective arousal, whereas other questionnaires have included this domain [75-77]. It is apparent that the lack of inclusion of subjective arousal in definitions of dysfunction has moved the focus of diagnosis away from women's subjective experience. 1. PSYCHOPHYSIOLOGICAL STUDY OF SUBJEC- TIVE SEXUAL AROUSAL AND INCREASES IN VAGINAL VASOCONGESTION The evidence to follow, shows that the vast majority of women diagnosed with “female sexual arousal disorder” over the past 25 years, under laboratory conditions of viewing erotic videos (which frequently fail to subjectively arouse them and may cause negative emotions), nevertheless, show prompt genital vasocongestion comparable to sexually healthy women. In three studies genital responsiveness to sexual stimuli, measured by vaginal pulse amplitude (VPA) as assessed with vaginal photoplethysmography, was compared between premenopausal women with and without sexual problems [42, 46, 78]. A fourth study using the same measure compared responses between pre- and postmenopausal women with and without sexual arousal disorder diagnosed according to DSM-IV criteria [54]. Interestingly women with dyspareunia were found to respond with equal VPA increases to visual sexual stimuli as do women without dyspareunia [78]. No differences were found in VPA between a group of 12 women with hypoactive sexual desire, a group of 12 anor- 2. COMPONENTS OF SEXUAL AROUSAL The following two tables show the various components of women's sexual arousal. Table 4 lists conscious components. Table 5 lists aspects organized by the woman's involuntary (autonomic) nervous system that are outside of conscious awareness. Table 4 : Conscious components of women’s sexual arousal Components Characteristics Reference LOE Cited Subjective sexual arousal/ sexual excitement. Correlates with appraisal of stimulus and its context. Often poor correlation with genital vasocongestion. 49 42,43,44,45,46, 47,48,49 4 3b, 4 Modulated by thoughts and by emotions Not necessarily increased by performance demand. 36,41,51,52 79 2b, 3b, 4 4 Direct awareness of genital engorgement, throbbing, tingling. Correlates poorly with subjective arousal. Highly variable amongst women 80 4 Sexual sensations and sexual excitement from stimulating engorged structures. This provides an indirect confirmation of genital engorgement. Repetitive sexual stimulation to non -engorged structures leads to irritation, discomfort 73 5 859 Table 5 : Components of sexual arousal outside of conscious awareness Component Physiological Mechanisms References and Levels of Evidence Vasocongestion of vulval structures. Neurogenic vasodilation mediated at least in part by NO from autonomic nerve endings, endothelium and smooth muscle of sinusoids within clitoral bulbs, rami, shaft and head, and periurethral spongy tissue dilate. Vaginal vasocongestion with increased lubrication. Vaginal arteriolar dilation from VIP, NO and other unknown neurotransmitter, possibly NPY-associated veno-constriction leads to increased interstitial fluid formation from vaginal submucosal capillaries. Fluid filters through epithelial cells onto lumen with less potassium and more sodium than in the non-aroused state. Is increased by performance demand in healthy women. Is increased by activation of sympathetic nervous system. Can be increased by anxiety, including sexual anxiety. Correlates variably with subjective arousal in healthy women. Correlates poorly with subjective arousal in women with arousal disorders. Correlates with negative emotions in women with arousal disorders LOE Cited 81 5 82,83,84 5 85 5 79 86,45 44 42,49, 86, 87 42,43,88 4 4 4 4 3b, 4 85 5 3. MODEL OF WOMEN'S SEXUAL AROUSAL a) DSM-IV The following model attempts to show the two parallel processes - one conscious and one unconscious. It also shows highly variable modulation of subjective arousal by genital feedback and robust modulation by the woman's concurrent thoughts and emotions (Figure 3). Female Sexual Arousal Disorder (FSAD) 4. BRAIN IMAGING IN WOMEN DURING SEXUAL b) ICD-10 Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity an adequate lubrication, swelling response of sexual excitement. This disturbance causes marked distress or interpersonal difficulty. Failure of genital response. AROUSAL Magnetic resonance imaging of sexually healthy women willing to be imaged during sexual arousal from watching an erotic video, delineates areas of the brain active during sexual arousal. Of interest, the activation in the areas concerned with organizing and receiving afferent input from the genital reflexes, including the hypothalamus correlates very poorly with the women's rating of their subjective arousal. This is in contrast to men where there is high correlation between activation these areas and their rating of sexual arousal. Again, the rather minimal importance of genital feedback in women as they rate their overall subjective experience of arousal is emphasized [89]. In women, the principle problem is vaginal dryness or failure of lubrication. Female Sexual Arousal Disorder 2. RECOMMENDED DEFINITIONS OF WOMEN'S SEXUAL AROUSAL DISORDERS (BASED ON EVIDENCE IN TABLES 4 AND 5) a) Combined Genital and Subjective Arousal Disorder 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 (vulval swelling, lubrication). II. WOMEN’S SEXUAL AROUSAL DISORDERS b) Genital Sexual Arousal Disorder Complaints of absent or impaired genital sexual arousal. Self-report may include minimal vulval swelling or vaginal lubrication from any type of sexual stimulation and reduced sexual sensations 1. CURRENT DEFINITIONS OF WOMEN'S SEXUAL AROUSAL DISORDERS 860 Figure 3. Model of women’s sexual arousal settings improved the orgasmic experience only in those women with markedly abnormal psychophysiological testing [88]. Thus clinical subtyping produced a heterogeneous group. This study contrasts to the previously mentioned study whereby none of 29 women with DSM-IV diagnosed arousal disorder (i.e. also genitally focused disorder), showed abnormal vasocongestive reponse [54]. Of note, the study showing heterogeneity included only women with acquired genital loss - within the previous 6 years. Of these women with acquired genital sexual arousal disorder, some clearly had abnormal vasocongestion demonstrable by currently available methods. Others may have had vascular deficit observable by more sensitive methods in the future. However, it may well be that factors other than the degree of vasocongestion, e.g. to do with sexual sensitivity of the engorging structures, underlie the loss of genital responsivity in some of this clinical subgroup of acquired genital arousal disorder. A very recent study of 31 sexually healthy women and 31 with arousal disorders - subtypes, acquired genital, long term subjective and combined, identified reduced vasocongestive response to erotic stimuli only in the subgroup with acquired genital arousal disorder [43]. from caressing genitalia. Subjective sexual excitement still occurs from non genital stimuli. c) Subjective Sexual Arousal Disorder 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. 3. PSYCHOPHYSIOLOGICAL DATA TO SUPPORT CLINICAL SUBTYPING Clinical subtyping of women complaining of lack of sexual arousal allowed further investigation of 34 women meeting the criteria for genital arousal disorder. These were postmenopausal estrogenized women who maintained healthy sexual interest and arousal from non-genital sexual stimulation. Since genital stimulation had been their former means of reaching orgasm, most were currently anorgasmic or experienced markedly delayed and reduced intensity orgasms. Psychophysiological studies with vaginal photoplethysmography showed markedly reduced genital vasocongestion in 13 women, moderately reduced in 8, and normal vasocongestion in 11 women. Interestingly, the double-blind placebocontrolled use of 50mg sildenafil under laboratory 861 Parasympathetic nerves from S2,3,4 release neurotransmitters including NO mediating vasodilation, and ACh blocking noradrenergic vasocongestive mechanisms pre or post junctionally and acting on the endothelium to release NO. D. BIOLOGICAL BASIS OF AROUSAL AND DESIRE This autonomic neuroanatomy is based on comparable nerves in the man. How accurate all of this is for women is currently unclear. There is some recent clarification of the parasympathetic input to vaginal vasocongestion. Stimulating the second and third sacral anterior nerve roots in a conscious young woman who was paraplegic, by using an intradural implanted Finetech/Brindley stimulator activated by radio signals, caused significant increases in vaginal congestion as measured by vaginal photoplethysmography [91]. Stimulating the fourth sacral root failed to increase the vaginal congestion. Women with spinal cord injury below the T10 to L2 spinal cord levels where the sympathetic nerves leave the cord, are able to vasocongest from psychogenic sexual stimuli [92]. I. CENTRAL NEUROENDOCRINE BASIS The neuroendocrine basis of arousal is poorly understood. A limited understanding stems in part from sexual effects of medication with known or partially known mechanisms of action. It is suggested that more than 30 neurotransmitters, peptides and hormones are involved - the most clinically relevant being noradrenaline, dopamine, oxytocin, serotonin acting via 5HT1A, 5HT2C receptors, being “prosexual”, prolactin, GABA and serotonin acting via other receptors tending to be sexually negative. These neurotransmitters and peptides in turn are modulated by sex hormones - estrogens, androgens and progesterone. Work with brain imaging of women during sexual arousal points to some areas of the brain being involved in cognitive appraisal, namely, the frontal orbital and anterior cingulate areas, and others being involved in the emotional response to arousal, including the rostral anterior cingulate. Other areas involved in the organization and perception of genital reflexes include the rostral anterior cingulate and posterior hypothalamus [89]. 2. NEUROTRANSMITTERS OF THE GENITAL RESPONSE Nitric Oxide, ACh, VIP appear to be prime neurotransmitters contributing to clitoral engorgement [81]. The results of female genital tract smooth muscle cell cultures suggest a role of cAMP dependent pathways via Prostaglandin E1, VIP and betaadrenergic receptors. The uncongested vulval structures are perceived to be under a tonic control via adrenergic and possibly peptidergic sympathetic vasoconstrictor mechanisms. Functional α1 and α2 adrenergic receptors in human clitoral and vaginal smooth muscle are present [93]. Hormones influence vascular function by genomic and non-genomic means, by endothelial dependent and independent means. II. GENITAL CONGESTIVE RESPONSE 1. AUTONOMIC INNERVATION The genital arousal (i.e. vasocongestion), response involves the sympathetic and parasympathetic nerves. It is thought that pelvic sympathetic postganglionic neurons primarily release noradrenaline and adenosine triphosphate ATP, but some release acetylcholine (ACh), NO and VIP. Nerves from the more caudal sympathetic ganglia release noradrenaline and probably neuropeptide Y to produce expected vasoconstriction. However, sympathetic fibers in the hypogastric nerve pass through the ganglionic relay stations in the pelvic plexus and can produce vasodilation of vulval congestion as well as the opposite [90]. Regarding vaginal smooth muscle relaxation, there is a neurotransmitter, the identity of which remains illusive. Although it is thought that VIP and possibly NO are involved [82, 83] in vaginal smooth muscle relaxation, there remains a non-nitrergic NANC response - not associated with any known neuropeptides or purines [84]. Also, the agent for contraction of nonvascular vaginal smooth muscle involved in orgasm is not known. 862 the woman's feelings towards her partner at that time, the safety and privacy of the situation. E. ASSESSMENT OF WOMEN’S SEXUAL DYSFUNCTION • Enquire if the problem(s) is lifelong or acquired : i.e. was there a time when the sexual problems were not present. Lifelong dysfunction necessitates more detailed psychosexual enquiry regarding childhood, adolescence and past relationships. I. COMPREHENSIVE SEXUAL, MEDICAL AND PSYCHOSOCIAL HISTORY Acquired dysfunction necessitates careful enquiry into the context (psychological and medical), surrounding the onset of the dysfunction. The woman's detailed account of her sexual difficulties is crucial as many different types of problems give rise to sexual symptoms. This comprehensive history is summarized in Table 6. Note there are predisposing, precipitating and maintaining etiological factors. • Establish if the problems are situational or generalized (e.g. arousal may be minimal with her partner but prompt with her own self-stimulation/masturbation). Situational problems suggest an absence of organic disruption of the sexual response. 1. COMPONENTS OF SEXUAL ENQUIRY • Establish the sexual difficulties in the woman's own words (e.g. cannot become aroused, always has pain with intercourse). Situational problems may be adaptive - logical to the problematic context and this has obvious therapeutic relevance. • Clarify the context when activity is attempted, including the adequacy of sexual stimulation, • Establish the rest of her sexual response cycle (sexual interest, arousal, orgasm, satisfaction, and Table 6 : Components of a comprehensive sexual, medical, psychosocial history 863 freedom from pain associated with sexual stimulation or intercourse). • Interpersonal issues • Lack of useful sexual stimuli • Establish her partner's sex response cycle. • Lack of useful sexual context • Enquire about the reaction of both partners to the sexual difficulties. • Psychological issues within the woman herself, e.g. 2. COMPONENTS OF MEDICAL ENQUIRY - negative self-image Assessment of the current and past medical background is strongly recommended for all sexual dysfunctions - even when the concern is situational. - feelings of shame, guilt 1. Establish current general health with systems enquiry. - partner sexual dysfunction 2. Establish current mood and mental health: note impact of any anxiety/depression on sexual dysfunction. - dyspareunia 3. Clarify current medications/substance abuse. The following nine questions in Table 7 may be helpful for the initial assessment of low desire/interest : - past negative experiences or abuse • Expectation of negative outcome, e.g. - poor sexual skills - emotionally negative outcome 4. Document past medical, psychiatric, surgical history. 3. COMPONENTS OF PSYCHOSOCIAL HISTORY Table 7 : Questions to clarify the complaint of low sexual interest Assessment of the psychosocial and psychosexual history is strongly recommended for all sexual dysfunctions : • Nature and duration of current relationship. • Dynamics of current interpersonal relationship. • Clarify any negative/coercive/abusive experiences (physical, sexual or emotional). • Societal values/beliefs that are impacting on the sexual problems. • For most sexual problems, especially those that are lifelong, the following further components are necessary : - Identify any past pattern of sexual relationships. - Clarify the woman's sexual experiences as a teenager (alone/partnered). - Clarify developmental history, particularly relationships with parental figures, siblings, traumas and losses. • How long have you had these concerns with respect to your sexual desire/interest? • Currently would you feel some interest in sex from something that was potentially erotic to you, e.g. a picture, book, movie, dancing? • For many women, feeling emotionally close and able to trust their partner is as important to them as sensing their partner is physically sexually attractive. How is the emotional intimacy with your partner – the trust, ability to be honest, ability to share feelings? • Especially in longer-term relationships, women often start out a sexual experience without any feelings of sexual desire. However, they can respond to their partner or to other sexual stimuli. So I need to ask you about the circumstances when you consider being sexual, or when your partner is instigating. Can you describe the circumstances? • Can you in time, respond to the sexual touching and stimuli and then feel some desire to continue? • Can you stay focused and are you able to guide your partner as to what pleases you - does anything negative happen (the situation is not what you want or intercourse is attempted too soon, or there is pain). II. COMPONENTS OF ENQUIRY FOR INDIVIDUAL DYSFUNCTIONS 1. SEXUAL • Do you sometimes have positive sexual thoughts, sexual daydreams and fantasies (even though you may not act on them)? • Many women self-stimulate – is that something you still INTEREST DISORDER/HYPOACTIVE do from time to time? SEXUAL DESIRE • What would your answers have been to the above ques- Enquire re possible etiological factors : tions previously? 864 Note, some questions concern sexual arousal given a lack of arousal precludes accessing desire during the sexual experience. III. PHYSICAL EXAM A careful focused pelvic exam is needed in the circumstances listed below. However, it must be remembered such an examination is intrusive and may elicit emotions linked to past coercive, abusive and/or painful sexual experiences. It is highly recommended that the procedure is explained in detail, what will and will not occur and the woman's understanding and consent obtained. She may prefer her partner or a nurse to be present. Details of the nature of examination are given in Chapter 16 under the heading of “Sexual Pain Disorders”. 2. AROUSAL DISORDERS Evaluate the following components of arousal : • Mental sexual excitement e.g. from - reading, viewing, hearing erotica - stimulating the partner - receiving sexual stimulation to non-genital and genital areas - deliberate sexual fantasy or recall of sexual memories • Direct awareness of genital congestion - tingling, pulsing, throbbing in response to the above stimuli, vaginal lubrication • Indirect evidence of genital congestion - progressively intense sexual sensations from direct massaging of vulval structures with her fingers, partner's fingers, partner's body, oral stimulation, dildo, penile vulval contact. • Cognitive and Affective Evaluation : - Clarify her thoughts (Is she distracted, feeling sexually substandard, worried the outcome would be negative, aware that the situation is not safe from STDs or pregnancy or will confirm again her infertility, is she feeling used, not being considered) - Clarify her emotions (Is there sadness, embarrassment, guilt, awkwardness, displeasure [e.g. from the giving of stimulation to the partner], are there feelings of attraction to the partner ?) • For women with dyspareunia - an educational exam is often recommended - see section on “Pain Disorders”. • For women diagnosed with vaginismus, done in progressive stages once fear of vaginal entry has lessened with therapy an educational exam is recommended. • For women with genital arousal disorder. Information will, of course, be limited because the genitalia are in non-aroused state but estrogen deficiency or more rarely, disease such as connective tissue disorder, can be identified. • For women with combined arousal disorders. Likely there will be no abnormality - nothing arouses these women subjectively be it written, visual, nongenital physical stimulation and the evidence to date is that their genital response is healthy. Nevertheless, a “normal” exam is highly informative to the woman. It is also possible that a woman with combined arousal disorder goes on to become estrogen deficient - adding physical vulval atrophy to her longstanding problems of disconnection from genital events. 3. ORGASMIC DISORDER (FOD) • Clarify exactly what is unsatisfactory :- its absence, delay, reduced intensity. • Are there also concerns with arousal, i.e. is this arousal disorder by definition ? (If so - evaluate as above) • Is there fear of letting go control ? • Is the degree of trust and safety she needs to let go control present ? • What does she fear may happen ? • For women with neurological disease affecting pelvic nerves where a detailed neurological genital exam is also necessary, clarify light touch, pressure, pain, temperature sensation, anal and vaginal tone, voluntary tightening of anus, and vaginal and bulbocavernosal reflexes. • For women with history of pelvic trauma • For women with any disease potentially affecting genital health. 4. DYSPAREUNIA AND VAGINISMUS • For women with acquired and lifelong orgasmic disorder even if otherwise healthy (a normal examination is of therapeutic value). The detailed assessment follows in the section on sexual pain. 865 Physical examination may not be needed on some occasions, e.g. the woman with low sexual desire or interest for sex but who is otherwise completely healthy. The complete physical exam is necessary for the woman who has symptoms additional to those sexual, e.g. fatigue, irregular menses. For women with chronic medical conditions, a general exam will be necessary to address mobility requirements for sexual activity, and also cardiac and respiratory status, given the physical demands of orgasm and intercourse. The presence of stomas, catheters, urinary diversions, or parts of the body that are giving rise to chronic pain and influencing sexual enjoyment can also be identified. recommended to aid diagnoses. IV. LABORATORY INVESTIGATIONS • MEDICAL surgical, psychiatric conditions, medications, substance abuse. These are frequently unnecessary, but need to be done when there are relevant symptoms or findings in the general medical assessment. However, investigations may be needed specifically for sexual symptoms, e.g. the vaginal discharge may need to be examined with microscopy and culture and sensitivity when dyspareunia is considered to be potentially due to infection. If sensitive and accurate assays for androgens are available, they can be ordered to support a clinical diagnosis of insufficient androgen activity. Given that women's sexuality is contextual, there is some difficulty with the concept of diagnosing a woman as having a sexual dysfunction when the primary problem appears to be the “sexual context” in which the sexual exchange occurs. However, she is reporting that dysfunction is present even though factors other than her own sexuality need to be highlighted. It is therefore strongly recommended to include contextual descriptors within each diagnosis. If psychophysiological investigation is available, this may be very helpful especially in identifying the common inattention to apparently healthy genital response [64]. However, the role of psychophysiological testing in the clinical arena is currently unclear Mild, moderate, marked : in the absence of distress, a disruption of sexual response (or lack of interest) still has epidemiological but rather little clinical importance. In addition : a) Clarify if the Dysfunction is Lifelong or Acquired - see page (859). b) Clarify if a Dysfunction is Situational or Generalized - see page (859). c) Clarify Contextual Factors : · PAST : negative upbringing/losses/trauma (physical, sexual, emotional), past interpersonal relationships, cultural/religious restrictions. • CURRENT : interpersonal difficulties, partner sexual dysfunction, inadequate stimulation and unsatisfactory sexual emotional contexts. d) Clarify the Degree of Distress VI. FORMULATION OF SEXUAL PROBLEMES V. ESTABLISHING THE DIAGNOSES Comorbidity of sexual dysfunction in women is common, especially sexual interest disorder (hypoactive sexual desire) and sexual arousal disorders. The following algorithm, Figure 4, parts 1 and 2, is Construction of the woman's sex response cycle noting the problematic areas is highly recommended (for example, see Figure 5). 866 Figures 4 a Figures 4 b 867 Figure 5. Sex response cycle of women with acquired sexual interest and subjective arousal disorders after infertility sexual dysfunction. Such understanding also has major treatment implications and may guide a comprehensive, multidimensional treatment approach. F. PSYCHOLOGICAL ETIOLOGICAL FACTORS INVOLVED IN AROUSAL AND DESIRE DISORDERS IN WOMEN I. PSYCHOLOGICAL DEVELOPMENT This section will focus on certain psychological factors potentially involved in the etiology of desire and arousal disorders. The focus here will be on depression, anxiety and personality factors. By focused inquiry into past and current psychological states, the clinician elucidates the predisposing, precipitating, and perpetuating factors implicated in the woman's sexual difficulties, and is able to formulate a case conceptualization. It must be noted at the outset that there is a paucity of prospective, randomized controlled trials in this area, largely attributable to the ethical limitations involved in doing such research. In addition, two seemingly orthogonal research streams have focused on the impact of psychological factors in this way : one has employed controlled, laboratory investigations that typically involve an experimental manipulation; the other involves quasiexperimental clinical investigations of individuals with the psychological feature of interest. An attempt will be made to integrate the findings from these two streams of research. Studying psychological and personality factors may lead to a better understanding of the mechanisms involved in the development of The development of personality and psychological profile begins before birth and continues life-long, involving a complex interplay between biological, psychological, and socio-cultural forces. One might consider a diathesis-stress model in which psychological factors present early in development interact with life events to influence a particular sexual profile. Alternatively, it is possible that the order of causation is reversed such that a particular sexual difficulty may trigger or exacerbate psychological distress. Given that the predominance of research examining the relationship between psychological factors and sexual dysfunction relies on correlational analyses, determining the order of causation is not possible. II. GENERAL PSYCHOLOGICAL FEATURES Studies that have examined general psychological profiles have consistently found higher rates of psy- 868 chological distress in women with sexual dysfunction [95-100] as shown in Table 8. Where conflicting findings arise, these can usually be attributed to different methodologies employed, as interview assessment results in higher prevalence compared to paperand-pencil tests. Worry, on the other hand, while it is associated with many psychiatric disorders and especially anxiety, did not appear to be a risk factor for sexual desire problems in nonclinical populations [109]. V. CLINICAL STUDIES ON SEXUAL FUNCTION IN WOMEN WITH ANXIETY DISORDERS III. THE ROLE OF ANXIETY IN SEXUAL FUNCTION AND DYSFUNCTION Whereas most of the research examining the relationship between anxiety and sexuality has explored anxiety in women with sexual dysfunction, some research has looked at sexuality in women with anxiety disorders - see Table 9. The literature suggests a higher incidence of sexual difficulties in women with anxiety disorders compared to nonanxious women. For example, women with panic disorder [110, 111] and obsessive compulsive disorder [111] show lower sexual desire than healthy controls. Women with OCD are more likely to experience sexual difficulties, in particular avoidance of sexual activity, than women with generalized anxiety [112]. Social anxiety has also received attention as it relates to sexual function. Compared to women with panic disorder, a small retrospective study found that those with social phobia have more difficulties with orgasm than sexual aversion [114]. However, in a very large sample of college students [113], as well as in a clinical sample of 40 socially phobic women [115] social anxiety was very strongly related to sexual difficulties, fewer sexual partners, and greater unhappiness in sexual encounters. Anxiety has been conceptualized as consisting of a chronic somatic component of overactivation, a cognitive component focusing on perceived lack of control, and a shift of attention to internal somatic cues. In terms of the subjective experience, anxiety can be characterized as a condition of anxious apprehension [102]. Research examining the role of anxiety in sexual dysfunction has included both clinical studies and controlled laboratory investigations. Early psychodynamic theories placed a heavy emphasis on anxiety as an important etiological predictor of sexual dysfunction. In Kaplan's influential model of etiology [103], performance anxiety was both a consequence of sexual activity, and a cause of sexual dysfunction, and reflected the failure of psychic defenses to prevent the emergence of anxiety. Based completely on clinical experience, anxiety and sexual arousal were thought to be incompatible with each other. The empirical literature, however, suggests such conclusions to be overly simplistic. Overall, the empirical results provide evidence of a significant relationship between anxiety and sexual difficulties. Sexual disorders including impaired arousal, desire and satisfaction are common complications of various anxiety disorders. Looking at the causal relationship of panic disorder and sexual dysfunction, data indicate that there is either a coincidence of panic syndrome and sexual phobia/aversion or, more often, a panic experience during sexual arousal. The results tend to confirm hypotheses claiming that sexual phobics with panic syndrome are not really afraid of sexuality, but rather of panicking and losing control [119]. Van den Hout and Barlow (2000) reviewed the empirical literature on sexual disorders and anxiety disorders. In general they found that anxious patients tend to selectively attend towards perceived threat whereas patients with sexual dysfunction focus their attention away from relevant cues [116]. IV. CLINICAL STUDIES ON ANXIETY IN WOMEN WITH SEXUAL DYSFUNCTION The role of anxiety as a key etiological agent in the genesis of sexual disorders has been highlighted in a number of clinical research studies, as shown in Table 9. One review found high levels of anxiety in sexually dysfunctional individuals [104], however, there was a high degree of variability in the amount and quality of anxiety across individuals with different sexual disorders [117, 118]. Sexual aversion tends to correlate highly with acute anxiety [106]. More recent studies on women with general sexual dysfunction [107] as well as those with low sexual desire [108] find higher rates of depression and anxiety compared to sexually healthy women. 869 Table 8. Studies investigating general psychological features and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 870 Table 8. Studies investigating general psychological features and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 871 Table 9. Clinical studies investigating anxiety and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 872 Table 9. Clinical studies investigating anxiety and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 873 Table 9. Clinical studies investigating anxiety and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 874 ch must aim to identify the precise cognitive, affective, and/or physiological processes by which anxiety and women's sexual function are related. The ongoing work by Janssen & Bancroft exploring a dual-control model of sexual excitation and inhibition in women as well as men, may clarify any role of anxiety in women's predisposition to sexual inhibition and to sexual excitement [11]. VI. LABORATORY STUDIES ON ANXIETY IN WOMEN WITH AND WITHOUT SEXUAL DYSFUNCTION The notion that anxiety is associated with sexual dysfunction has been challenged by a number of wellcontrolled laboratory investigations. Different techniques for manipulating and inducing anxiety have been explored, and sexual arousal has been assessed by both subjective (e.g., self-report questionnaire) and psychophysiological (e.g. vaginal photoplethysmograph) techniques, as shown in Table 10 VIII. THE ROLE OF DEPRESSION IN SEXUAL FUNCTION AND DYSFUNCTION In sexually healthy women, anxiety-inducing techniques have been found to significantly increase psychophysiological sexual arousal [79, 120, 121, 123]. Specifically, it appears as though anxiety's mechanism of action may be via increased sympathetic nervous system (SNS) activity given that exercise [86] and other methods of SNS-facilitation [45] enhance physiological sexual arousal. Subjective sexual arousal, however, has been shown to be increased [79] decreased [121], and unaffected [4547, 86] by these techniques. In women with heterogeneous sexual difficulties, anxiety significantly improved genital sexual congestion [121, 123, 124]. In contrast, heightened SNS activity facilitated genital sexual congestion in women with low sexual desire, but impaired it in women with orgasm disorder, and there was no effect on subjective sexual arousal [46]. Taken together, these results suggest that techniques which facilitate SNS activity may have promise for improving genital congestion - but not subjective sexual arousal. Loss of interest or pleasure is a hallmark feature of depression. By extension, sexual interest is vulnerable to the effects of depression, and impaired sexual desire has been found in the majority of patients with depressed mood since the mid-1960s [125]. The opposite may also be true in that disruption in sexual function may affect mood. As with anxiety, two streams of research, one conducted in a laboratory and other in clinical samples, has attempted to explore the relationship between depression and sexual function - see Table 11. IX. CLINICAL STUDIES ON DEPRESSION IN WOMEN WITH SEXUAL DYSFUNCTION Derogatis and colleagues administered the Symptom Check-List Revised 90 (SCL-90R) to 325 male and female outpatients seeking treatment for sexual dysfunction [95]. Of the 126 women, 50% were assigned a psychiatric diagnosis. Specifically, major depression was found to be a feature of women with orgasm disorder and sexual pain disorder. SchreinerEngel and Schiavi [96] compared women with impaired sexual desire to sexually healthy controls on current and lifetime affective symptoms. Although no patient met criteria for major depression at study entry, women with impaired desire were twice as likely as controls to have a history of major depressive disorder. Interestingly, the major depressive episode always either coincided with or preceded the sexual dysfunction onset. VII. CONCLUSIONS : ANXIETY AND SEXUAL FUNCTION IN WOMEN Whereas anxiety historically has been linked to impaired sexual function, more recent laboratory evidence suggests potential enhancement of the physical response, at least by some types of anxiety. However, high levels of clinical anxiety are related to impaired sexual function in the real life situation. Clearly, investigations that aim to clarify the mechanisms by which acute and chronic anxiety affect sexual function are needed. Moreover, resear- 875 Table 10. Laboratory studies investigating anxiety and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 876 Table 10. Laboratory studies investigating anxiety and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 877 Table 11. Clinical studies investigating depression and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 878 Table 11. Clinical studies investigating depression and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 879 X. CLINICAL STUDIES ON SEXUAL FUNCTION IN DEPRESSED WOMEN XIII. PERSONALITY VARIABLES AND WOMEN’S SEXUAL FUNCTION The literature on sexual function of depressed individuals is complicated by the effects of antidepressant medication. Bartlik and colleagues reviewed the literature on sexual dysfunction secondary to depressive disorders, concluding that loss of desire is a consistent consequence of major depression, regardless of antidepressant use [131]. Kivela found a strong association between low sex drive and depression in Finnish women in their 60s [126]. Decreased libido was also found to be a key feature in depressed patients with Bipolar disorder [125, 128]. Most recently, Kennedy and colleagues examined a consecutive series of 79 women with Major Depression and found that half the sample experienced problems with sexual desire and arousal [129]. Compared to the research on psychiatric disorders and women's sexual dysfunction, much less attention has focused on the role of personality disorders - see Table 12. An extensive exploration into the role of personality factors in female orgasm failed to find any major associations [132]. With respect to hypoactive sexual desire disorder, Hartmann and colleagues studied 52 consecutive women diagnosed with HSDD, and found significant disturbance with emotional stability and self-esteem [31]. Some authors have speculated that such difficulties are deep-rooted as opposed to acute reactions to the sexual difficulty. Women with histrionic personality disorder were compared to non-histrionic women and were found to have significantly lower sexual assertiveness, greater erotophobic attitudes toward sex, lower self-esteem, and greater marital dissatisfaction [133]. Despite lower sexual desire, more sexual boredom, and greater orgasmic dysfunction, this group displayed higher sexual esteem and increased likelihood of entering into an extramarital affair compared to non-histrionic women. Women with borderline personality disorder show a similar pattern in that despite sexual depression and dissatisfaction, there were higher rates of sexual esteem and sexual assertiveness compared to non-borderline personality disorder women [134]. XI. LABORATORY STUDIES ON DEPRESSED MOOD IN WOMEN WITH SEXUAL DYSFUNCTION Frohlich and Meston compared depressed to nondepressed college women using the Beck Depression Inventory. The depressed group showed higher rates of desire for sexual activity alone, despite more problematic sexual arousal, orgasm, pain, satisfaction, and pleasure. This novel finding was explained by the speculation that masturbation may reflect a reliable form of pleasure compared to partnered sexual activity [130]. Sensation seeking, a characteristic of individuals with narcissistic personality, has been found to be related to increased sexual desire and arousability, but is not associated with marital or sexual satisfaction [135]. In an extensive review which included individual differences pertaining to women's sexuality, Andersen and Cyranowski [136] report that developmental factors are important to consider when examining the relationship between personality and sexuality. Specifically, older women seeking treatment for mixed sexual dysfunctions had higher Neuroticism scores [137] whereas in younger women, the trait of Extraversion was more prominent [138]. XII. CONCLUSIONS : DEPRESSION AND SEXUAL FUNCTION IN WOMEN Compared to the literature on anxiety and sexual function, a strong, and clear relationship exists between depressed mood and sexual dysfunction in women. Given the retrospective design in the studies reviewed, it is difficult to determine the order of causality, however, some have speculated that depression may play a causal role in the development of female sexual dysfunction. This literature is complicated by the high number of medicated depressed patients, thus precluding clear conclusions. 880 Table 12. Clinical studies investigating personality variables and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 881 Table 12. Clinical studies investigating personality variables and sexual dysfunction in women. SD = sexual dysfunction, LOE = level of evidence 882 XIV. CONCLUSIONS : PERSONALITY FACTORS AND SEXUAL FUNCTION IN WOMEN G. MANAGEMENT OF DESIRE AND CORMORBID SUBJECTIVE AROUSAL DISORDERS From the available literature it is apparent that personality features of low/fragile self-regulation and selfesteem, as well as histrionic personality relate to impaired sexual desire. Cluster B traits of histrionic and borderline personality are associated with increased sexual esteem, despite impaired sexual desire and dissatisfaction. Additionally, developmental factors must be taken into account when considering the role of personality in women's sexual function and dysfunction. Given that personality factors (i.e., trait of an individual) are much less amenable to change than psychological reactions (i.e., state of an individual), assessment of personality as it might influence sexual health is important. I. PSYCHOLOGICAL TREATMENTS Psychological therapy remains the mainstay of management of women's sexual dysfunction. Making deliberate changes in thoughts and attitudes and in behaviour can lead to not only changes in the mind (feelings and emotions) but changes in the body's physiology - including sexual response. Psychological management contains various elements. Sensate focus techniques originate from the work of Masters and Johnson [139] and consist of exchanging physical touch, moving from non-sexual to sexual touching. They resemble the systematic desensitization approach common to behaviour therapies, in that anxiety-reduction is incorporated throughout the process. Sex therapy may also address the woman's distractions during sexual stimulation, promote more varied and/or more prolonged sexual stimuli, and encourage the couple to guide each other as to their required sexual stimulation. Safety, privacy, optimal timing of sexual contacts can also be addressed. Cognitive-behavioural therapy (CBT) adds attention to cognitive restructuring of distortions and myths that may be related to the sexual difficulty, and places a heavy emphasis on “in session” and homework assignments. The behavioural changes may include addressing the lack of required sexual stimuli and/or addressing the sexual context, including privacy, safety, what has occurred prior to attempting sexual activity, what will follow, as well as concurrent demands, e.g. sleep, care of children. Couple therapy is commonly a component of, or adjunct to sex therapy, and focuses on interpersonal issues such as communication training that affect the sexual relationship. Psychodynamic therapy has also received much attention as it relates to female sexuality. This therapy tends to focus on issues in the woman's past developmental period that influence current sexual function, especially her arousability (factors governing the information processing of the sexual stimuli). Particular attention to family of origin as well as the parental relationship can often provide important insights into the current sexual difficulty. Schnarch proposes that as part of systemic therapy, sexual differentiation (i.e., ability to balance desire XV. OVERALL CONCLUSIONS Given the links between low desire/impaired subjective arousal, with depression, clinical anxiety disorders and certain personality attributes, the following components of the psychological assessment are recommended. As the studies reviewed are mostly levels 2b and 4, the grade of recommendation is B-C. • Assessment of women's sexual function should always take into account psychological and personality factors that might affect or be affected by the current sexual difficulty. • Regardless of antidepressant use, depression is consistently related to sexual dysfunction, in particular low sexual desire. The clinician must assess mood, and associated symptoms of depressive disorder, in women presenting with sexual difficulties. • The temporal relationship between psychiatric symptom and sexual difficulty should be assessed in order to determine cause or effect. • Given the conflicting data on the role of chronic versus acute anxiety in women's sexual dysfunction, a clear assessment of the severity, chronicity, and degree of anxiety is necessary to understand what role, if any, anxiety plays in maintaining the current sexual complaint. • In order to distinguish if a personality or psychological feature is influencing a given sexual concern, and thus amenable to change, the clinician should assess if such features are reflective of deep-rooted personality factors (i.e., trait), or short-term reactions (i.e., state). 883 criptions of diagnostic criteria which prohibit replication, failing to include long-term follow-up data, and incomplete descriptions of the therapy technique utilized, again prohibiting replication [141]. This research area also has not historically employed treatment manuals or assessment instruments with good psychometric properties. Lack of recognition of this topic as a high priority by major granting agencies, and minor incentive for pharmaceutical companies to fund psychological efficacy studies may explain the paucity of well-controlled randomized trials of psychological therapy. for contact with desire for uniqueness) is important for relationship and sexual health [140]. II. REVIEW OF EFFICACY OF PSYCHOLOGICAL THERAPY This section will review psychological treatments for hypoactive sexual desire disorder and combined desire and arousal disorders, including studies cited in the review by Heiman and Meston [141] as well as additional investigations that have been published since 1997. Most are of Levels 3, 4, and 5 evidence. A literature search resulted in only one relevant randomized controlled trial. 2. MASTERS AND JOHNSON SEX THERAPY In 1970 Masters and Johnson published their efficacy studies conducted on 500 couples seen in their institute [139]. Briefly, treatment was administered 2-3 times/week by a male-female therapist duo, and outcome was assessed with one item (i.e., success or not) by these clinicians. Success rates reached 72% for female anorgasmia and 98% for vaginismus, with a mere 5% relapse rate after five years. Given the expensive, intensive, and unfeasible nature of Masters and Johnson's model of sex therapy, there has been no replication of their findings. However, this body of research stimulated an attempt at exploring which component(s) of their therapy were responsible for improving sexual function. In a large clinical trial of 365 married couples presenting to a sex therapy clinic with heterogeneous sexual complaints, 65% of the couples responded to behaviour therapy with improved outcomes. Specifically, the amount of sensate focus was most strongly predictive of a positive outcome [144]. However, it is unclear which sexual complaints specifically benefited from treatment and the outcome measure was simply a clinician-judgement of the primary sexual complaint. 1. DIFFICULTIES WITH OUTCOME RESEARCH Research on efficacy of sex therapy is challenged by a number of factors that make this type of research difficult and inconclusive. (1) Women's sexual complaints may take the form of formal DSM-IV diagnoses such as lack of, or diminished sexual desire or interest, or pain during both genital and non-genital sexual activities [142, 143]. However, women's sexual complaints also include dissatisfactions that do not involve observable or perceived physical impairment but rather, unobservable factors related to pleasure, enjoyment, satisfaction, or passion. The International Classification of Diseases - 10, acknowledges this by noting the “anhedonia/lack of sexual enjoyment” category [56]. Although these components are recognized by the treating clinician, they tend not to receive detailed attention in efficacy research. As such, our outcome research may be targeting and/or detecting changes in aspects of the sexual response that are less important for women than these more ubiquitous aspects. (2) Given the biopsychosocial complexity of the sexual response, it is difficult for researchers to agree on what endpoint variables should be assessed as indicators for response to treatment. (3) Researchers also have not reached consensus on the degree of change which denotes improvement versus no change. Historically intercourse frequency was the gold-standard indicator of sexual function ; however, exclusive focus on this variable ignores the rich complexity of sexuality that cannot be captured by a simple frequency count of one particular act. In their review, Heiman and Meston (1997) criticize this literature for employing small sample sizes, failing to include adequate control groups, lacking randomization, unclear des- III. SEXUAL DESIRE DISORDERS Most women complaining of low desire are in fact suffering from a concomitant sexual arousal disorder [35, 36, 38-40]. However, with a model of lubrication difficulties as the central focus in arousal complaints, lack of wanting sexual experience, for whatever reasons, has been termed low sexual desire. In fact, as reviewed in Basson (2002), the data support the conclusion that women can enjoy healthy and rewarding sexual lives, despite minimal awareness of desire, and the latter is not typically their primary 884 motivation, depression, and anxiety, and fewer dysfunctional negative cognitions - see Table 13. incentive for seeking sexual activity [61]. Few published efficacy studies exist for sexual desire disorder. Numerous published descriptions of treatments for this condition exist, but few meet criteria for evidence-based treatment [140]. Basson (1996) reviewed important factors to consider when treating low desire that appears to be beyond the common lessening with relationship duration [152]. She highlighted the importance of attention to the emotional intimacy and other contextual factors that historically promoted healthy responsive sexual desire. In addition, management should address the cause of the non-rewarding outcome of the sexual encounter. Once these factors have been identified, they can receive focused attention and intervention. These claims are based on level 4 and 5 evidence [153]. Crowe and colleagues compared traditional sex therapy with marital therapy and relaxation training in 48 couples presenting with erectile dysfunction, low sexual desire, and anorgasmia. Although results suggest that the sex therapy improved self-reported desire, data were not examined by gender or by individual diagnosis [146]. The outcome data of Zimmer (1987) faced similar confounds in that although their treatment showed benefit of sex therapy over relaxation training, data were not examined separately by presenting problem [147]. Hawton employed a modified Masters and Johnson approach in his prospective, non-controlled study of a community sample of couples. Sexual desire difficulties were significantly improved in 56% of the couples following treatment, however 75% of the sample relapsed at 1-6 years post-treatment [148]. Hurlbert investigated the efficacy of orgasm consistency training for the treatment of female desire disorder [149]. Women received either standard sex therapy or sex therapy plus orgasm consistency training (directed masturbation) in addition to sensuality exercises, communication training and education. Both groups demonstrated greater sexual arousal, assertiveness, and satisfaction, but the combination group experienced greater overall improvement. The efficacy of CBT in women with sexual desire disorder has been examined in two studies [150]. McCabe found that CBT in a sample of women seeking treatment for mixed sexual dysfunction resulted in 54% of the sample retaining this complaint following treatment. However, the findings are limited in that a large number of the women had multiple sexual dysfunctions, and there was the absence of a comparison control group. In the only published study testing the efficacy of a psychological treatment for impaired desire against a control group, CBT was adapted to specifically target relevant causal factors implicated in impaired desire [151]. Only 26% of women with HSDD randomized to the CBT condition met diagnostic criteria for this disorder at post-treatment, and this stabilized to 36% at one-year follow-up. Compared to the control group, CBT also led to significant improvements in: the quality of the sexual and marital life, sexual satisfaction, perception of sexual arousal, dyadic adjustment and cognitions, sexual repertoire and pleasure, sexual self-esteem, IV. SEXUAL AROUSAL DISORDERS There are no published outcome studies focusing on the psychological treatment of arousal disorders in women. This may largely be attributable to the previously mentioned high degree of comorbidity between desire and arousal disorders, as well as desire and orgasm disorders. Recently, attention to one aspect of dysfunctional sexual arousal has increased. The success of vasoactive agents in the treatment of male sexual arousal (i.e., erectile disorder), has prompted a focus on women's genital congestion and the testing of similar vasoactive products. Lack of recognition of the need to distinguish impaired genital congestion from absence of subjective arousal (despite genital congestion) has limited progress in this area - see section on “Genital Arousal Disorder”. V. NON-HORMONAL PHARMACOLOGICAL TREATMENT OF LOW SEXUAL DESIRE The place of pharmacological management for women's complaint of low desire is unclear. Given the broad normative range of women's appreciation of “sexual desire” in sexually content women and the importance of subjective arousal once sexual stimulation has begun, which then generates sexual desire, the appropriate outcome criteria for any “desire drug” remain to be determined. Two studies have been reported - both with bupropion hydrochloride. A 12-week double-blind placebo controlled study 885 Table 13. Efficacy studies investigating effects of psychological therapy on female sexual desire disorder. SD = sexual dysfunction; LOE = level of evidence. 886 Table 13. Efficacy studies investigating effects of psychological therapy on female sexual desire disorder. SD = sexual dysfunction; LOE = level of evidence. 887 Table 13. Efficacy studies investigating effects of psychological therapy on female sexual desire disorder. SD = sexual dysfunction; LOE = level of evidence. 888 showed statistically significant benefit for nondepressed women with a spectrum of sexual complaints, including sexual aversion, low sexual desire, “low sexual excitement” and impaired orgasm. Whereas 19 of the 30 women with active drug improved - only one did so on placebo. Analysis was not performed separately according to diagnostic group [154]. Of a group of non-depressed women diagnosed with hypoactive sexual desire receiving bupropion hydrochloride in single-blinded manner, 29% responded. None had responded to an initial four-week placebo phase [155]. Larger placebocontrolled randomized trials of bupropion or other molecules altering the neurotransmitters known to influence desire, or more importantly, subjective arousability to sexual stimuli, including dopamine, serotonin and noradrenaline, are awaited. VII. CONCLUSIONS AND RECOMMENDATIONS Traditional sex therapy (with sensate focus) has been the most widely investigated psychological approach to treating hypoactive sexual desire disorder in women, and although efficacy rates are not as impressive as those from Masters and Johnson's data, there is still some empirical support for this treatment. Additionally, there appears to be good data supporting the use of CBT in couples with hypoactive sexual desire. Clearly these results require replication. Partially due to the inherent difficulty in testing its efficacy, there are no randomized controlled trials of psychodynamic treatment, despite the clinical experience of its need and efficacy. There is very modest evidence of benefit from the use of bupropion HCl in some women with low sexual desire. Acknowledgement that sexual desire per se (as in sexual thinking, fantasizing, or needing to masturbate, awareness of sexual desire before any sexual stimulation begins), has a broad normative range amongst women is important. What may have greater therapeutic benefit is a focus on women's distress around having little sexual interest/motivation/incentives for sexual activity. Lastly, there are VI. FACTORS ASSOCIATED WITH GOOD PROGNOSIS IN SEX THERAPY Based on clinical observation and experience, as well as a few empirical studies [156, 157], there are several factors that appear to be related to successful treatment outcome. These are summarized in Table 14. Table 14. Factors associated with positive outcome in sex therapy trials. Factors associated with positive outcome in sex therapy trials Study Level of Evidence Overall quality of the couple’s non-sexual relationship Hawton & Catalan, 1986 [158] 4 Couple’s motivation to enter treatment Whitehead & Mathews, 1986 [159] Hawton, Catalan, & Fagg, 1991 [160] 4 2c Degree of physical attraction between partners Hawton, 1995 [156] 5 Absence of major psychiatric disorders Hawton, 1995 [156] 5 Evidence of early homework compliance Hawton, 1995 [156] 5 Attention to systemic issues in the relationship Besharat, 2001 [161] Milan, Kilmann, & Boland, 1988 [162] 2a 2c Male partner’s motivation to obtain a successful outcome Hawton, Catalan, & Fagg, 1991 [160], Hirst & Watson, 1997 [163] 2c 4 Amount of sensate focused completed in the last week of treatment Sarwer & Durlak, 1997 [144] 2c 889 congestion is only recent [35, 43, 88, 164, 165]. Early evidence suggests that history alone may not delineate which women will respond to phosphodiesterase inhibitors [88]. Whereas benefit is expected in some women with autonomic nerve damage [166], women with presumed vascular etiology are difficult to identify. A small recent laboratory based placebo-controlled study of women clinically diagnosed with physical/genital arousal disorder suggested only some might benefit from Sildenafil [88]. The use of the vaginal photoplethysmograph appeared to identify those women. Of 34 postmenopausal estrogenized women with acquired genital arousal disorder only those with clearly abnormal vasocongestive response to an erotic visual stimulus appeared to show benefit in terms of ease of genital arousal and orgasm under laboratory conditions [88]. no published psychological efficacy studies for women with any type of arousal disorders. It is recommended that the focus on loss of subjective sexual arousal is made in future studies. In summary : • Benefit from psychological treatment has been unclear in part due to outcome measures that reflect male sexual desire but show a broad normative range across sexually healthy women • Improvement in subjective arousal and excitement is rarely addressed despite the data confirming its importance relative to genital congestion. • Cognitive-behavioural techniques show efficacy in women with low desire - Grade B-C and deserve research attention in the treatment of women with subjective arousal disorder. Sildenafil has not been shown to be of benefit to women with broad spectrum sexual dysfunction including arousal disorder, in either large [35] or small [167] studies. Women identified as having DSM-IV arousal disorder (note : there the focus is on absent lubrication and swelling, i.e. the subgroup now classified as having genital arousal disorder) but no DSM-IV diagnosis of hypoactive sexual desire disorder did show benefit beyond placebo in a very recent study [164]. The Table 8 summarizes studies to date (Table 15). • Despite the frequent clinical occurrence of nonsexual psychodynamic factors negatively influencing women's sexual arousal and interest and the frequent recommendation for psychodynamic treatment, due to inherent difficulty in testing efficacy, there have been no randomized controlled trials. The recommendation for this treatment is thus Grade D. • Techniques that improve homework compliance early-on may lead to better outcomes with sex therapy - Grade D. • Prognostic factors related to the interpersonal relationship such as quality of the non-sexual relationship, couple's motivation for treatment, degree of physical attraction, and systemic issues in the relationship are important predictors of positive response to treatment in sex therapy - Grade B-C. II. USE OF TIBOLONE FOR GENITAL AROUSAL DISORDER Studies of women who were not identified as having sexual dysfunction do show benefit over placebo (and some studies show benefit over other forms of HRT) in terms of sexual satisfaction, genital responsivity, coital comfort, subjective arousal and sexual desire/interest - see Table 9. H. MANAGEMENT OF GENITAL AROUSAL DISORDER III. THE USE OF ESTROGEN FOR GENITAL AROUSAL DISORDER I. USE OF PHOSPHODIESTERASE INHIBITORS FOR GENITAL AROUSAL DISORDER For women who are estrogen deficient, local estrogen treatment is highly recommended as first line treatment for genital arousal disorder - please see section on “Estrogen Treatment”. Delineation of the likely small subgroup of estrogen replete women complaining of difficulty with genital 890 Table 15 : Pharmacotherapy for women’s genital arousal disorder: use of sildenafil Key: * ** *** **** SFQ GEQ SCI IFSF Thirty-one item sexual function questionnaire. Global efficacy question Spinal cord injury Index of female sexual function 891 Table 16 . Pharmacotherapy for women’s genital arousal disorder: tibolone 892 though testosterone levels fluctuate substantially in men during the day, these have not been clearly related to changes in libido or well being, though chronic deficiency of testosterone has. I. MANAGEMENT OF ORGASMIC DYSFUNCTION The impetus for treating women who complain of decreased libido with testosterone comes from the assumption that this hormone will play a similar role in women's sexuality as it does in men's. Cross-sectional and cohort studies of sexual function and testosterone levels are inconclusive - see Table 17. Experimental evidence of sexual benefit from testosterone administration is suggestive but not conclusive - see Table 18. It is not clear from any human data if sexual benefit from testosterone is via the androgen receptor or solely via the estrogen receptor from aromatization of testosterone to estradiol. The major effect of testosterone, therefore, could simply be to decrease SHBG and thereby make estrogen more available. This remains an unanswered question. To add further complexity, it is of note that women with complete androgen insensitivity syndrome mostly report healthy desire and response [176]. In clinical practice most women complaining of lack of orgasm have comorbid lack of subjective arousal [40]. However, high/adequate arousal that is not released with orgasm(s) may cause distress to the woman. It frequently causes distress to the partner. For situational orgasm disorder (orgasm with masturbation but not with the partner) : • the focus of therapy is on the relationship, especially the issues of trust and safety such that the woman can be vulnerable. The partner may need information regarding the woman's sexual function. Both may need to hear that women usually need to guide the partner as to the stimulation they need. For generalized orgasm disorder : • Cognitive behavioural therapy is recommended. This focuses on promoting changes and attitudes in sexually relevant thoughts. Behavioural exercises traditionally prescribed include direct masturbation, sensate focus and desensitization - Grade B. I. RANDOMIZED CONTROLLED STUDIES OF SHORT TERM TESTOSTERONE THERAPY • Anxiety reduction techniques are best suited for anorgasmic women only when sexual anxiety is coexistent - Grade C. Table 18 summarizes studies investigating shortterm sexual benefit of testosterone treatment. A much quoted early study used testosterone enanthate producing total T levels several times the upper female normal -- comparable to those seen in severe polycystic ovary syndrome or hyperthecosis [180]. Several other studies have reported improvement in a variety of parameters related to sexual activity and satisfaction. Though the doses used were more moderate, all produced blood levels which were supraphysiological or for a few, close to the upper end of the normal range for premenopausal women-- which may be definitely supraphysiological for postmenopausal women. Note a biologically optimal testosterone range for postmenopausal women has not been established. • Components of treatment programs including education, communication skills, Kegel exercises are recommended only as adjuncts to CBT - Grade C. • No pharmacological agents can be recommended. (Only open labeled studies have suggested benefits e.g. with bupropion, granisetron) - Grade B. J. ROLE OF ANDROGENS IN WOMEN’S SEXUAL FUNCTION AND DYSFUNCTION Hormones are of obvious critical importance for sexual and reproductive function. Follicle maturation, ovulation and pregnancy maintenance depend on pituitary and gonadal hormones. Puberty does not occur in the absence of the normal rise in levels of these hormones and the onset of conscious sexual feelings occurs at puberty. Mood and well being are substantially affected in many women by cyclic shifts in estrogen and progesterone [175]. In contrast, Another early study employed implants of testosterone and estradiol which produced high normal total T levels [181]. However, a recent study used a testosterone matrix patch to administer transdermal testosterone to women already receiving CEE. This delivery method has the advantage of producing relatively steady-state levels and avoids the initial very 893 Table 17 : Level 4 evidence from cross sectional and cohort studies of sexual response and testosterone values note: limitations of testosterone assays in these studies STUDY DETAILS Cawood,1996 [22] 141 women aged 40-60 in representative community survey. No hormonal parameter correlated with any measurements of sexual desire and response LOE 4 Dennerstein, 2002 [72] 438 women observed over 8 years across the menopause transition. Sexual response and desire correlated with estradiol levels and not with testosterone. 2b 59 women aged 60-70 not identified as having sexual problems. Free testosterone correlated with levels of sexual desire 4 Nathorst-Boos, 1992 [178] No correlation with sexual variables and T or 700 women with hysterectomy +/- or minus BSO +/- ERT. free T (and no differences between the two groups). 2b Conaglen, 2003 [179] Compared to controls, hirsute women had lower sexual 2a 29 hirsute women given cyproterone acetate and estradiol for 12 months. desire at baseline. One-third experienced further reduction of desire during antiandrogen treatment. Self-esteem increased in the majority. No significant correlation between any androgen levels and desire. Leiblum, Bachmann, 1981 [177] high levels produced by testosterone enanthate and other esters as well as the oral preparation, testosterone undecanoate. In the patch study, the delivery of 300 µg T daily showed sexual benefit and produced elevated total T levels and free T levels near the top of the menstrual age normal range [182]. Of interest, later data analysis found that in women aged up to 48, outcome did not differ between active and placebo whereas in the over 48 age group, the difference was significant. A possible interpretation would be a greater contribution of purely biological factors in diminished sexual interest in women after the fifth decade. Further investigations of the interaction of age and other factors with women's diminished sexual interest to better define differences in etiology, are needed. In another recent study using testosterone undecanoate, testosterone levels were clearly supraphysiological [183]. low desire dated from menopause. An increase in frequency of desire did not reach statistical significance, sexual arousability was not measured and scores in the BISF-W responding to interest/desire did not change significantly. There were, however, highly significant correlations between changes in bioavailable testosterone and changes in interest using the SIQ. The unmeasured androgenic activity of the methyl testosterone itself, as well as borderline high bioavailable testosterone levels are the major concerns precluding any recommendation regarding clinical use of this formulation based on this study. Moreover, the women with natural menopause were not receiving a progestin for the duration of the study [185]. A recent study reported the beneficial results of administration of transdermal testosterone administration to premenstrual age women complaining of diminished sexual interest for which neither psychological nor contextual cause had been found [70]. However both total testosterone and free testosterone index were elevated in the treatment group. The study population appears to have been somewhat heterogeneous. Hirsutism ratings increased only slightly, however the insensitivity of such ratings is discussed below in reference to Shifren, et al. Metabolic safety parameters (lipids, insulin, glucose) were not reported - see Table 18. The combination of methyl testosterone and esterified estrogens has been the most widely used preparation in the United States, though studies reporting efficacy re improved sexual function are recent. This preparation compared to estrogen alone was studied in an RCT which found improvement in sexual functioning with the combination [184]. A very recent level 1b 4-month trial of 1.25mg methyl testosterone plus 0.625mg esterified estrogen showed increase in the total score for desire/interest in a new validated questionnaire (SIQ) (measuring level of desire, distress re low desire). The women were naturally or surgically menopausal and their In summary, though an effect of testosterone administration to women complaining of diminished sexual interest and satisfaction to improve these 894 Table 18 : studies examining short-term benefit of testosterone therapy 895 2) Relationship of symptoms to the established biological actions of the hormone. outcomes has been found by most, though not all, RCTs, this constitutes level 2b evidence in view of use of different preparations, low numbers, short duration, different outcome measures between studies and statistical significance on only some of multiple measures. It is not known if short-term therapy could allow long-term benefit and there is zero long-term safety data. 3) Reversal of symptoms upon administration of the hormone in doses which establish normal blood levels. Effects at pharmacological doses do not establish a deficiency state. None of these criteria are fully met with testosterone administration to women with diminished sexual interest or other sexual dysfunction. A specific level of testosterone in women which can be considered diagnostic of androgen deficiency has not been established. While some studies have claimed that women with diminished interest are more likely to have low testosterone levels than women without this complaint [196, 197], these are limited by the fact that results on women with diminished libido were compared to laboratory normal ranges rather than to a matched control group i.e. this is level 4 evidence. Other studies have found no correlation between androgen levels and sexual interest or activity [22, 179, 198]. A study of women in their twenties and thirties presenting with complaints of low desire compared to control women, also did not find a difference in free testosterone levels [199]. In premenopausal hirsute women, treatment with the antiandrogen cyproterone acetate combined with CEE, though it lowered free testosterone levels did not alter sexual parameters other than being associated with increased coital frequency. This was based on comparison to baseline [200]. A recent study has shown similar androgen and SHBG values in sexually healthy naturally menopausal women and women with surgical menopause complaining of low sexual desire [201]. II. RANDOMIZED CONTROLLED STUDIES OF DHEA THERAPY Despite documented progressive loss of DHEA and DHEAS in women (as well as men) [190], from late 30s onwards, results of DHEA supplementation to improve sexual health have been conflicting - see Table 19. Measurement of adrenal androgens in otherwise healthy women with and without sexual dysfunction is needed. III. ANDROGEN DEFICIENCY SYNDROME Although an “androgen deficiency” syndrome in women has been described, this does not meet usual criteria in endocrinology for establishment of a deficiency state, which may be formulated as follows : 1) Symptoms regularly associated with low levels of the hormone as determined by measurement of hormone levels. Table 19 : Placebo controlled trials of DHEA Study Details Loe Arlt, 1999 [191] 24 women with androgen insufficiency. Sexual interest and satisfaction increased after 4 months on 50 mg DHEA daily giving low physiological levels for 4 months 1b Lovas, 2003 [192] 39 women with Addison’s disease. No change in sexual desire and satisfaction or response with 25 mg daily DHEA for 9 months. 1b Hunt, 2000 [193] 24 women with Addison’s disease. No sexual benefit from 50 mg DHEA daily for 3 months. 1b Barnhart, 1999 [194] 66 perimenopausal women with reduced well being and reduced sexual desire. No sexual or well being benefit compared to placebo after 3 months. 1b Baulieu, 2000 [195] 140 women 60-79 years old with general aging symptoms Sexual activity, arousal, satisfaction but not desire increased compared to placebo only in women over 70 years, after 12 months. 896 1b One further study did show lower free testosterone levels in women with lifelong absence of sexual interest [202]. Unfortunately, hormones were measured only once ; the relation to a lifelong problem is therefore uncertain. Evidence for lower testosterone in women with diminished sexual interest does not meet even level 4 criteria in view of inconsistent results, diversity of populations studied as well as absence of controls in some studies. be measured. Estimating testosterone activity from the measurement of testosterone metabolites (glucuronides) is not yet standardized. Free testosterone is reduced by about 50% by many oral contraceptives and may also be reduced by concomitant administration of glucocorticoids. In the case of oral contraceptives, this reduction has not been convincingly shown to result in reduced sexual desire or activity [203-205]. The RCTs reporting that some women do report higher sexual desire with administration of testosterone in controlled studies did not establish that the women who responded had lower testosterone levels than non-responders or than women without sexual complaints. Of equal importance, studies have not so far clarified what factors predict response, other than age over 48 years [182]. IV. MEASUREMENT OF TESTOSTERONE To some degree conflicting data may be due to problems in measuring testosterone including lack of assay specificity and circadian variation. Free testosterone, preferably measured by equilibrium dialysis -- unfortunately rarely available in clinical settings -- correlates more closely with the biological effects of the hormone than does the total because most of the circulating testosterone is bound to SHBG which prevents diffusion into tissues. Accordingly the free fraction should be measured. Analogue assays for free-testosterone are unreliable and not recommended. Free testosterone can be estimated from the SHBG, albumin and total testosterone. However, the measurement of total testosterone is also problematic. Whatever method is chosen, it must be adequately validated. There are, unfortunately, no simple assays of total testosterone that have been shown to produce reliable results at the low levels found in many women. Direct immuno assays are not problem free either, particularly because of cross-reactivity with other steroids, markedly so at low testosterone concentrations. V. TESTOSTERONE PRODUCTION BY THE POSTMENOPAUSAL OVARY The question as to whether testosterone levels are lower in ovariectomized women throughout postmenopausal life, continues. There is level 2b evidence on both sides [201, 206]. The belief that levels are indeed lower has led to an assumption that removal of the ovaries peri or post menopause is associated with decreased libido, however, this has not been validated in appropriate studies. Nor has it been determined whether women who have undergone surgical removal of their ovaries are more likely to respond to exogenous testosterone than those with natural menopause. It is difficult to make these direct amino assays both accurate (by various techniques) and cost effective. The preferred method is liquid chromatography with mass spectrometry. Weakly bound testosterone, ie “bioavailable testosterone” may correlate slightly better with hormone action than the free testosterone but it is less widely used and no specific relevance to evaluation of women's sexual complaints has been established. VI. PATIENT SELECTION As no studies have established that testosterone blood level is predictive of response, patient selection is problematic. Furthermore, many women with diminished desire who are treated with testosterone do not respond. This is in contrast to treatment of recognized deficiency syndromes in which virtually all treated individuals respond. In women under age 48 in the patch study, response to placebo and testosterone were identical [182]. A further major complicating factor is that much testosterone activity is derived from intracellular production of testosterone from ovarian and adrenal precursors [190]. This intracellular testosterone cannot 897 rity of the effects of administered testosterone on women's skin and hair. For example, the study reported by Shifren, et al [182] found no difference in hirsutism ratings but did find significantly more frequent removal in treated as compared to placebo women, suggesting that the rating system was insufficiently sensitive. Crossover design further complicated safety assessments as all subjects received active for 6 out of 9 months and the skin and hair changes may be permanent. A further limitation of such studies is that they have generally lasted only several months while appearance of these testosterone effects can be gradual over a period of years. That many women who present for medical evaluation of acne, hirsutism and androgenic alopecia have testosterone levels at the high normal range indicates that a small increase in blood level might engender such changes to a distressing degree. VII. CONCLUSIONS RE TESTOSTERONE THERAPY At this time, knowledge is simply the observation reviewed above, statistically significant in some relatively short term studies, that some women who complain of low sexual interest and response do show increases in related study endpoints on testosterone regimens which produce slightly or overtly supraphysiological levels. This observation is important, considering the high incidence of reported low sexual interest and loss of arousability and the subjective distress it sometimes, though not always [1], produces. However at this time, evidence-based criteria for patient selection do not exist. 3. METABOLIC EFFECT OF EXOGENOUS VIII. EVIDENCE RE RISKS OF ANDROGEN SUPPLEMENTATION TESTOSTERONE In PCOS and other clinical syndromes, testosterone excess has been associated with hyperinsulinemia, with unfavorable lipid changes, with hypertension and with an increased later risk of cardiovascular disease. Generally these complications are observed in women who are significantly obese. While it appears that hyperinsulinemia is usually the cause of hyperandrogenism, there are some reports of situations in which hyperandrogenism causes insulin resistance [208]. Further research is needed to be certain that testosterone administration does not increase the risk of these metabolic dysfunctions in some women. 1. ENDOGENOUS HIGH LEVELS OF TESTOSTERONE A variety of conditions such as polycystic ovary syndrome, congenital adrenal hyperplasia and others are associated with testosterone excess in women [207]. In these conditions, testosterone levels vary from borderline to severely elevated. Experience with these conditions demonstrates potential adverse effects of androgens on women. The changes in the appearance of hair and skin are direct effects of testosterone and the resulting effects are particularly disturbing for women. Greater sebum production, is the initial event leading to acne. Testosterone also alters hair follicle activity, inhibiting it in the case of scalp hair and stimulating it on specific areas of face and body including upper lip, chin, sideburns and cheeks, midline of chest and abdomen, periareolar area, lower back and legs. Axillary and pubic hair appear in girls at puberty as a direct result of increased adrenal and ovarian production of testosterone. Increased testosterone action can stimulate extension of pubic hair down the thighs and up toward the umbilicus. Differences in scalp and body hair are important determinants of perception of gender. 4. EXOGENOUS TESTOSTERONE IN ESTROGEN DEPLETE WOMEN An important safety issue which has not been addressed in any studies is the effect of testosterone administration to menopausal or otherwise estrogen deficient women without concomitant administration of estrogen (and progesterone if uterus is intact). This issue has particular urgency in light of the recent report of the Women's Health Initiative (WHI) finding increased risk in women on a fixed dose combination of conjugated equine estrogens and medroxyprogesterone acetate. The wide publicity which these results received has resulted in many women discontinuing estrogen replacement [209]. Thus some women may want to receive testosterone without estrogen replacement. There are several areas of potential concern. First, the safety of replacing 2. DERMATOLOGICAL EFFECTS OF EXOGENOUS TESTOSTERONE Unfortunately, published studies have not used adequate methodology to assess the incidence and seve- 898 androgens but not estrogens in women deficient in both, is entirely unknown, as no studies have used this regimen. Second, if we assume hypothetically that sexual activity will be increased by the testosterone, it is not clear that atrophic vaginal tissues will permit comfortable and safe intercourse. With the availability of vasoactive agents such as sildenafil, there is the possibility that more frequent intercourse with partners with firmer erections may tear or otherwise damage an atrophic vaginal mucosa. 5. CONCLUSIONS RE [211]. However what is ordinarily referred to as “stress” in daily life (such as coping with a demanding boss) cannot be assumed to have the same effects. Interestingly, one study of women undergoing divorce or separation showed them to have a slight increase in testosterone compared to controls without marital difficulty [212]. Although parameters related to sexuality were not measured, it is generally assumed that stress reduces libido in women and so here there may be a dissociation between testosterone and changes in desire. RISKS AND SAFETY OF In stress induced hypothalamic amenorrhea the ovary is relatively quiescent so that levels of estrogen and testosterone are usually low. While clinical experience indicates that many women with hypothalamic amenorrhea also have diminished sexual interest, no systematic studies have been reported. EXOGENOUS TESTOSTERONE In view of intracellular conversion to estrogen, long term safety re venothrombotic events, breast cancer and cardiovascular disease, is unknown. Since adverse effects on the lipid profile can be seen with orally administered progestins possessing androgenic activity, methyl testosterone may have the same potential. Despite the availability of the preparation for many years, safety data is quite limited. The dose of MeT used in a recently reported study [185] was found in another study to lower HDL cholesterol [210]. X. ALGORITHM FOR ASSESSING AND MANAGING INVESTIGATIONAL ANDROGEN THERAPY Current knowledge regarding treatment of low desire or response with testosterone is not sufficient to permit patient selection on evidence-based criteria. However, given that some affected women urgently request treatment and the observation that testosterone is sometimes efficacious, it is appropriate to offer tentative recommendations. However, these can only be considered for post menopausal estrogenized women, and only in the short term. Definitive guidelines cannot be formulated in the present state of knowledge. Accordingly, these recommendations should be regarded as provisional and subject to revision as research proceeds and are only Grade C-D. A major intent is avoidance of harm and inappropriate patient selection. The recommendations are given as an algorithm, progressing from one question to the next only if the previous answer is “yes”. The purpose is to assess the suitability of short-term androgen therapy. In the patch study [182] lipid parameters, fasting glucose and insulin were unaltered. However, effects of administration of exogenous testosterone to women, particularly long-term, on metabolic safety parameters such as lipids, glucose and insulin need further study. Such effects may be specific for preparation and route of administration. Accordingly evidence on safety is level 4 in view of short followup, inconsistencies between studies and incomplete or inadequate safety outcome measures. IX. EVIDENCE RE PSYCHOLOGICAL STRESS AFFECTING ANDROGEN PRODUCTION Physical stress is well known to increase adrenal production of cortisol, mediated by an increase in ACTH release by the pituitary. However, this is an acute response and it is less clear that chronic stress produces sustained elevations of levels. Because ACTH also stimulates adrenal androgen secretion, it is often assumed that chronic stress in women may induce or exacerbate hyperandrogenism. Whether this is common or clinically significant is unproven. Surgical stress does increase female androgen levels First, does the patient understand and accept that in the absence of studies longer than several months, long-term safety is currently unknown and the treatment that is about to begin cannot currently be extended beyond one year ? If so : 1) Does the patient complain of persistently decreased sexual interest, response and satisfaction and is she postmenopausal ? 899 2) Is she using systemic ERT ? K. THE ROLE OF ESTROGEN IN WOMEN’S SEXUAL RESPONSE AND DYSFUNCTION 3) Has patient and clinician taken into account normative changes with relationship duration, life cycle and the broad range of sexual interest and desire across women ? 4) Did the patient previously have a higher level of desire and feel satisfaction with sexual activity? I. ESTROGEN AND VULVOVAGINAL HEALTH : SEXUAL SYMPTOMS OF DEFICIENCY 5) Is there absence of psychosocial causes of the sexual dysfunction ? This would include issues within the woman herself, e.g. the need for control, or suppressed anger or difficulty feeling any emotions, interpersonal difficulties with the partner as well as contextual problems such as lack of privacy or safety, lack of appropriate erotic stimulation and atmosphere ? 1. ESTROGEN EFFECTS ON EPITHELIA, BLOOD VESSELS AND GLANDS Estrogen has been demonstrated to have effects on all tissue components of the vulvovaginal area, including epithelia (skin, vaginal), skin appendages, blood vessels, nerves, and specialized glands. In summary, estrogen is a growth-promoting hormone and thus stimulates activity in all the above tissues. Estrogen promotes maturation and proliferation of the epithelia, enhances vascularity and increases blood flow, and stimulates glandular secretions (e.g., Bartholin's gland). 6) Is the history negative for factors which might limit sexual response such as fatigue, medication effect, chronic illness, chronic non-sexual pain, dyspareunia or mood disorder ? 7) If the woman has a partner, is he or she free of sexual dysfunction ? Partner dysfunctions should be addressed before considering androgens for the woman. In turn, the decline in estrogen levels as occurs postmenopause, is associated with reversal of the above effects. This is evidenced as thinning of vulvovaginal epithelium, diminished blood flow, and reduced activity of specialized glands. The prevalence of vaginal dryness is estimated to range from 12% to 34%, largely dependent on age. Factors other than vascularity (e.g., permeability of vaginal epithelial cells) may influence lubrication and/or dryness. Nerve endings releasing CGRP and other neurotransmitters are found on vaginal epithelial cells [82]. Although their function is unclear, they may potentially alter permeability. 8) Are total and free testosterone levels well below the upper limit of normal by a reliable assay ? 9) Is she free of androgenic skin and hair changes seborrhea, acne, hirsutism or alopecia ? 10) Is she willing to accept possible risk of such changes and the need for discontinuation of testosterone therapy should they occur ? 11) Is she willing to come for regular visits to monitor testosterone therapy ? 12) Will the condition of genital tissues permit comfortable intercourse ? The vaginal epithelium is an exquisite bioassay for estrogen levels (an observation starting over 60 years ago with Papanicolaou). Thus, the vaginal smear utilized as a measurement of estrogenicity by its effect on the ratio of parabasal to intermediate to superficial cells [82], as in the Maturation Index, is confirmed by its direct correlation with estrogen levels [213]. Note : Biological factors such as removal of the ovaries or what exactly constitutes “low” free and/or total testosterone levels are not included in the algorithm. This is because such have not been convincingly shown to predict response to treatment. Further data are needed before there can be any recommendations regarding testosterone therapy for pre menopausal women. 2. SEXUAL SYMPTOMS FROM ESTROGEN LACK IN GENITAL TISSUES These physical changes can lead to sexual symptoms. These include vaginal dryness, dyspareunia, 900 reduced or absent pleasure from direct genital stimulation, urinary symptoms (especially urgency, frequency, and possibly incontinence), and predisposition to vulvar, vaginal, and lower urinary tract infections [214]. II. ESTROGEN LEVELS AND GENERAL MENOPAUSAL SYMPTOMS The majority of menopause-related studies have not utilized well-validated symptom profiles. The only symptoms that have been specifically related to the menopause transition are increasing vasomotor symptoms (VMS), vaginal dryness, and insomnia, and decrease in breast tenderness [217] (1b level evidence). Also, sleep disturbance is probably related to decline in estradiol levels [218, 219] (2b). The extent of vulvovaginal atrophy can vary from mild to extremely severe. The latter results in vaginal shortening and narrowing, and can also lead to introital stenosis. The result of this atrophy is to prevent penetration or at least to be a cause of significant pain and/or bleeding from attempted penetration. This can, in turn, result in escalation of problems for the woman and her partner. The woman with atrophy might avoid genital touch or intercourse even in the presence of subjective arousal for fear of experiencing pain or discomfort. Fear of hurting his partner or physical difficulty from introital stenosis or vaginal narrowing could exacerbate erectile dysfunction in the male partner. Needing to move quickly onto intercourse for fear of losing any erection further exacerbates the woman's difficulty. Either vulvovaginal atrophy or urinary dysfunction could reduce the woman's sense of attractiveness and, therefore, interest in sex [171]. Similarly, fear of incontinence or of urinary tract infection could also trigger the same avoidance response or lead to lack of subjective arousal and anorgasmia. 3. COMPLEXITIES There are remarkably few well-documented studies that have investigated changes in estradiol (E2) and estrone (E1) levels in relation to the final menstrual period (FMP) and/or symptoms [219-222]. Good data on estrogen and symptoms are anticipated from the Study of Women Across the Nation (SWAN), a multicenter, community-based, cohort study of US women and the menopause transition [221]. The Melbourne Women's Health Project (MWHP) has reported that sexual functioning (including sexual responsivity, frequency of sexual activities, and libido) declines concurrently with the decline in levels of estradiol, but not androgen, from the early to the late menopause transition [72] (2b). On the other hand, the Massachusetts Health Study II (MHS II) concluded that menopause status, but not estradiol levels, is related to some, but not all, aspects of sexual functioning. This could be due to menopause per se or to another factor, such as aging [223]. Indeed, the MWHP has also found sexual responsivity to decline with age. OF RELATIONSHIP BETWEEN GENITAL SEXUAL CONGESTION AND ESTROGEN ACTIVITY Despite evidence for the above symptoms in estrogen-deplete women, factors other than estrogen levels are involved. The percentage of estrogendeplete women without any of these symptoms even in the presence of easily observable atrophy is unknown. Possibly frequent sexual arousal and activity promotes continued genital health [177]. Psychophysiological studies show similar increases in vaginal congestion in response to sexually arousing erotic stimulation in both estrogen deficient and replete women [215]. Recent MRI studies suggest similar increases in clitoral volume in response to arousing erotic stimuli in pre and postmenopausal women [216]. Conclusion : Current evidence suggests specific menopausal symptoms are related to changing estrogen levels. III. ESTROGEN LEVELS AND SKIN SENSITIVITY An extremely common and distressing symptom beyond menopause is an intolerance or reduced awareness of sensual touching to all areas of the body. No scientific study has investigated this phenomenon. Nor is there data to support the clinical findings that in women of reproductive age, two-point discrimination is directly correlated to the stage of the reproductive cycle. That is, as estrogen levels escalate toward ovulation, two-point discrimination nar- Conclusion : There is excellent basic and clinical research to confirm a direct relationship between estrogen and vulvovaginal health, and sexual symptoms related to deficiency in some women. However, other poorly researched factors may prevent the presence of sexual symptoms despite estrogen deficiency. 901 rows, and then widens as estrogen levels drop premenstrually. This would imply a direct effect of estrogen on peripheral neural activity. Vasomotor symptomatic postmenopausal women suffer more sleep disturbances during the night [231]. In turn, estrogen therapy in symptomatic women reduces hot flash frequency and nighttime awakenings [234] (1b) There is evidence that estrogen increases rapid eye movement (REM) sleep [234]. Conclusion : Estrogen probably plays a major role in neural sensitivity. Research is necessary on other factors as well, such as androgen. One major, level 1b, randomized study has reported no benefit of continuous-combined estrogen plus progestogen therapy (EPT) on mood and sexuality. The large WHI trial of healthy postmenopausal women, found in its EPT arm of 16,608 women (aged 50-79 years) with an intact uterus that continuous-combined EPT (Prempro) did not have a clinically meaningful effect on health-related QOL [235]. However, this study has major design weaknesses (e.g., the average age of 63 is 12 years older than the menopause median age of 51; women with moderate or severe symptoms were discouraged from study participation; and no validated QOL instrument was utilized). Thus, investigators relied on surrogate biophysical tests with severe limitations (e.g., only one question was used to determine sexuality, the Modified Mini-Mental State Examination is too crude to measure cognition, the menopause symptom profile was unvalidated, and the Rand36 is a symptom profile not covering acceptable QOL domains). Recognizing potential deficiencies, a post-hoc intent-to-treat analysis was performed on symptomatic women aged 50 to 54. The intent-totreat analysis is satisfactory for the WHI primary objectives (i.e., cardiovascular and breast cancer outcomes), but it is unacceptable when evaluating a drug's mental effect to conclude lack of drug benefit in women not on the actual drug. This was an intentto-treat study, and almost half of the women in the study group discontinued therapy, although they remained in the treatment arm for determination of QOL results. The authors admitted in the text that “it is possible that differences were not significant at 3 years because of poorer adherence to assigned therapy” [235]. IV. ESTROGEN RECEPTORS IN THE BRAIN Estrogen effects on the brain can be mediated through receptor and/or nonreceptor mechanisms. These mechanisms have been well reviewed and can explain potential impact on well being, mood, and sleep [224]. The characterization and understanding of specific receptor activity has, for obvious reasons, been better defined in animals than humans [225]. V. ESTROGEN AND WELL BEING, MOOD AND SLEEP There are several impediments to examining the literature relating menopause and sense of well being, enhancement of mood, and relationship to sleep. These include poor definition of menopause status in study groups, failure to distinguish spontaneous from surgical menopause, lack of baseline hormone levels, disregard for concomitant medications, and variability in detail on combinations and permutations of replacement exogenous steroids. Instruments for measurement of domains of quality of life (QOL), mood, and sleep patterns are also usually poorly defined. For example, subtle changes in mood are difficult to extrapolate from the customarily utilized standard measures of depressive symptoms. Finally, it is not always apparent whether well being (QOL), mood, and sleep are enhanced by the well-established estrogenic effects on relief of hot flashes and night sweats. That is, studies need to control for hot flashes in analyses to determine any direct effect of menopause on mood [226-231]. Conclusion : Estrogen probably enhances mood, sense of well being, and sleep. Despite these difficulties, there is level 1a evidence demonstrating enhancements of mood with estrogen therapy [232], and level 1b level of evidence of improved quality of life and well being [233]. It can only be speculated that these effects, in turn, mediate a response in terms of enhanced desire or arousability [230]. VI. RISKS AND BENEFITS OF LOCAL AND SYSTEMIC ESTROGEN Sex-related symptoms from low levels of estrogen may be treated with estrogen, provided potential 902 ry indication for ET and EPT(1a). The US Food and Drug Administration (FDA) has subsequently generalized these data on Prempro to all estrogen-progestogen and estrogen-only preparations. A very recent multi-centred case controlled study of 155 consecutive cases of venous thromboembolism showed that oral but not transdermal ET was associated with risk of thromboembolism in post menopausal women [243]. Another very recent study, albeit nonrandomized, has confirmed the increased risk of both incident and fatal breast cancer with current use of estrogen therapy with a substantially greater effect for estrogen/ progestin combinations. The progestins involved included medroxyprogesterone acetate, norethisterone and norgestrel/levonorgestrel [244]. benefits outweigh potential risks. Based on level 1a evidence, clinicians are advised to prescribe the lowest dose of estrogen for the shortest duration consistent with treatment goals, benefits, and risks for the individual woman, taking into account quality of life issues [236] - Grade A. Effects may vary, not only among estrogens and mode of administration, but also from woman to woman. Vulvovaginal symptoms from local deficiency of estrogen may be treated with low-dose estrogen (1a. 1b & 2b) - Grade A. All estrogen types and modes of administration (pill, patch, vaginal preparation) are effective for this use. Vaginal estrogen preparations at doses used to treat atrophic vaginitis are unlikely to demonstrate any systemic effects. However, the possibility of systemic effects cannot be entirely excluded [237-240]. There is also 1b evidence of significant reduction and significance of urinary tract infection with an estradiol releasing vaginal ring [241]. Evidence suggests that the 17ßestradiol vaginal ring (estring), may be less likely to deliver systemic levels than the estradiol hemihydrate vaginal tablet (Vagifem) or the estrogen vaginal creams. The memory study of WHI (WHIMS) has concluded that continuous-combined EPT in women over age 65 (average age 71) demonstrates no cognitive value and may increase the rate of dementia [245, 246]. However, the absolute involvement in dementia is low, and the role of estrogen alone on cognition and dementia is still under investigation. All types and modes of administration of estrogen therapy and estrogen-progestogen therapy, that allow systemic absorption, including vaginal estrogen, are contraindicated in women with known or suspected pregnancy, history of hormone-sensitive carcinoma, unexplained uterine bleeding, liver disease (especially applies to oral estrogen), history of coagulopathies, and confirmed cardiovascular disease - Grade A. However, individual women, fully understanding the potential risks and benefits, may choose hormone therapy. Other sexual sequelae of low estrogen levels, including poor sleep, dislike of sensual touching, and lack of well being, can also be treated with low-dose estrogen - Grade C. Theoretically, transdermal estrogen may be a more appropriate choice than oral therapy, given the less effect on sex hormone-binding globulin and androgen activity. However, there is no scientific evidence to support this premise. It is well documented that systemic estrogen therapy (ET) can dramatically increase the risk of developing endometrial hyperplasia and carcinoma. Adding progestogen to ET (EPT) reduces that risk to the level of taking no hormones [242] (1b) - Grade A. Several studies, (levels 2a & 3b), have failed to demonstrate tumor recurrence in breast cancer patients on ET/EPT [247, 248]. A few studies in women previously diagnosed with breast cancer have actually suggested that ET/EPT may have beneficial effects [248-249]. However, a recent open randomised trial was stopped after 2.1 years due to increased numbers of new cancers in women on ET/ EPT [250]. The WHI study found that continuous combined EPT increased risks for breast cancer, coronary heart disease, thromboembolism, and stroke after 5 years [242]. The ET-only arm continues. Evaluating these results and those from other significant trials, The North American Menopause Society issued its Hormone Therapy Advisory Panel Report [236] which included among its basic recommendations for clinical practice that these data cannot be directly extrapolated to symptomatic perimenopausal women or to women experiencing early menopause (i.e., 40-50 years of age) or premature menopause (i.e., < 40 years), and that treatment of menopause symptoms (including urogenital symptoms) remains the prima- Potential side effects of systemic ET include uterine bleeding, breast effects (e.g., mastalgia), skin effects (e.g., rash, melasma), headache, and psychological effects (e.g., mood swings, irritability, fatigue, depression). By tailoring the hormone type, dosage, or route of administration, an appropriate therapy can typically be found for each woman. Conclusion : As with all prescription drugs, estro- 903 using various estrogen and progesterone combinations. The study was nonrandomized but in order to isolate the effects of tibolone alone (as opposed to using tibolone at baseline and other hormone preparations previously), analyses were restricted to women whose reported duration of use of tibolone was the same as the reported total duration of any type of therapy. The relative risk of breast cancer was 1.48. - the relative risk for other estrogen/progesterone combinations ranged between 1.53 and 1.97 (and between 1.19 and 1.65 for estrogen alone therapy). gen therapy offers potential benefits but also carries potential risks. The decision to prescribe should be based on an individualized risk-benefit profile and the wishes of the woman herself. VII. SELECTIVE ESTROGEN RECEPTOR MODULATORS One of the consequences of the WHI findings has been increased interest in selective estrogen receptor modulators (SERMs). These are chemically diverse substances without the steroid structure of estrogen but containing a tertiary structure that allows binding to α and β estrogen receptors. The exact mechanisms of the tissue selective, mixed agonist/antagonist action of SERMs is currently being clarified. These molecules potentially could retain estrogen's benefits and avoid most of the adverse effects. Of the two in current use - raloxifene and tamoxifen, unfortunately, there are no reported sexual benefits. There is no evidence of reversal of estrogen deficiency associated vulvar and vaginal changes. Increased well being/sleep/mood and decreased vasomotor symptoms attributable to estrogen are not seen. Future SERMs will hopefully have both the apparent benefits of raloxifene (antagonistic action on the endometrium, breast, along with absence of pro inflammatory effects and estrogen agonist action on bone), will also have estrogen agonist action on vulval and vaginal tissues and the ability to ameliorate vasomotor symptoms [251]. IX. EVIDENCE REGARDING PROGESTOGENS ON SEX AND MOOD While the evidence for a positive impact of estrogen on sex and mood is more substantial, progestogens (or more strictly progestins), on the other hand appear to have a negative impact. When a progestin is added to oppose estrogen therapy in women with an intact uterus, negative effects on sex and mood can occur. Although not all progestogens have the same effect, data are inadequate to recommend specific progestogens or estrogen-progestogen regimens that will minimize this effect [252-256]. Conclusion : Progestogens do not appear to offer added benefit to sexual function and some may have a negative impact on mood. L. CONTEXTUAL NATURE OF WOMEN’S SEXUALITY AND DYSFUNCTION VIII. TIBOLONE Contextual factors which influence women's sexual function can be considered the framework within which sexuality is experienced, and are important aspects for the clinician to consider. Previous sections have highlighted the roles of interpersonal, societal, and mental health contexts. Two further contextual dimensions are the sexual health of the partner and chronic illness. The National Health and Social Life Survey clarified that women reporting sexual difficulties also experienced higher rates of poor health and low physical well being [2]. In this section we consider the role of pelvic and breast cancer, diabetes, multiple sclerosis (MS), spinal cord injury (SCI), and heart disease. Finally, despite a relatively small literature, we address the entity of resilience to sexual dysfunction. This synthetic steroid with tissue selective estrogenic, progestogenic and androgenic actions has been shown to relieve sexual symptoms from vaginal atrophy, although the women studied were not those identified as having sexual dysfunction (recruitment was regarding bone density or vasomotor symptoms) [168-174]. Just a few studies [168, 170] reported significant improvement in sexual desire/interest in the women receiving tibolone. Of note, these prospective randomized trials have compared tibolone to placebo or to various formulations of estrogen and progestin therapy. The very recent million women study on breast cancer and hormone therapy [244] reported a significant excess of breast cancer for women currently using tibolone, as well as those 904 5. Has treatment for the chronic illness influenced the sexual response ? I. ROLE OF PARTNER SEXUAL HEALTH 6. Does the chronic illness limit the mobility necessary for caressing, self-stimulating, or engaging in intercourse ? Interpersonal factors play a key role in several theoretical explanations for women's sexual desire difficulties [145, 257-261]. A partner's sexual health is one specific interpersonal factor that has received recent attention. In a large, nationally representative sample of Swedish women (n = 1335) and men (n = 1475) aged 18-74, the male partner's early ejaculation and/or erectile dysfunction were found to significantly predict sexual well being [30], sexual disability [29], and the more global aspect of quality of life in the female partner. Interestingly, a longitudinal Australian study of determinants of sexual outcome in women transitioning menopause, showed increased “libido” - as in autoerotic practices, in the women whose frequency of sexual activity with their partner was reduced due to his sexual dysfunction [33]. This is reminiscent of another cross-sectional study of perimenopausal women which found a similar result - in that study the man was stated to have “physical limitations which restricted sexual activity” [223]. Table 20 illustrates the findings from these analyses. 7. Is there evidence of cardiovascular or respiratory compromise such that orgasm or movements of intercourse might be dangerous ? 8. Is the chronic illness associated with incontinence or stomas ? Despite the importance in obtaining such information, a well-established literature on each of these factors is scarce, in part due to difficulties inherent in recruitment. For example, in a study designed to investigate the effects of aortic surgery on female sexual function, 100 consecutive patients that had undergone aortic grafting 1-6 years earlier were mailed a questionnaire assessing recent sexual activity [263]. Thirty-nine patients had died, 15 were recently widowed, 15 reported being too unwell to participate, and of the remaining 31, only 7 completed the questionnaire. Age, patient life circumstances, and social stigma discouraging open discussion of sexuality, may be limiting research on the topic of sexual function in chronic illness. 1. PELVIC CANCER II. ROLE OF CHRONIC ILLNESS Whereas general physical health may be minimally affected by pelvic cancer, specific inquiry into sexual health reveals deleterious effects of the cancer and in particular, of its treatment - see table 21. Havenga et al reviewed the literature on sexual function after conventional surgery for rectal cancer and found that 24% of women reported reduced desire for sex, 38% had dyspareunia, and 28% noted difficulty reaching orgasm [265]. After a nerve-sparing mesorectal incision, few women report any new sexual dysfunction compared to pretreatment [265, 266]. Gynecological surgery (i.e., hysterectomy) for benign conditions does not significantly impair sexual desire [18]. However, for the treatment of cervical cancer, hysterectomy has been found to result in reduced vaginal lubrication, a shortened vaginal canal, lack of vaginal elasticity, and reduced pleasure from genital stimulation, in a retrospective Swedish study [8]. It is possible that these complaints were not exclusively due to the surgery given that many of these women also received intracavity or external beam irradiation. This group of authors also found that dyspareunia was more common for women who had external beam irradiation, and similar rates of Low sexual desire is a common complaint among women with chronic illness. Although low sexual desire may be present before the diagnosis of a chronic illness, the more typical picture is one of a global decrease in desire associated with the diagnosis or treatment of the medical illness. Moreover, the effects of a chronic illness on sexual function may be mediated directly by physiological mechanisms, or by psychological factors related to the illness. When considering the effects of chronic disease on women's sexual function, the following areas are deemed important : 1. Is there evidence of a biological disruption of the sexual response ? 2. Is there evidence of psychological consequences of the illness affecting the sexual response ? 3. Does the chronic illness increase fatigue or involve chronic pain ? 4. Have psychological reactions triggered a depressive episode ? 905 Table 20. Studies examining the role of partner sexual health in women’s sexual function and dysfunction. SD = sexual dysfunction; LOE = level of evidence. ED = erectile difficulties 906 Table 21 Studies examining the role of pelvic cancer and its treatment in women’s sexual function and dysfunction. SD = sexual dysfunction; LOE = level of evidence. 907 Table 21 Studies examining the role of pelvic cancer and its treatment in women’s sexual function and dysfunction. SD = sexual dysfunction; LOE = level of evidence. 908 orgasmic difficulties and trouble having intercourse were seen in women having surgery alone vs. those also exposed to intracavity radiotherapy [267]. Prospective studies, on the other hand, have failed to find any major persistent sexual dysfunction caused by radical hysterectomy for cervical cancer [268, 269], whereas radiation therapy was found to induce long-term sexual problems. Although vascular damage following radiation therapy is a common consequence of pelvic cancer in men, this has not been well studied in women. In general, vascular damage following radiation therapy in women has been associated with sexual pain [267, 270-271] ; and impaired vaginal lubrication [272]. Determining if these effects are due to vascular damage versus hormonal loss is complicated by the fact that such radiotherapy also leads to permanent ovarian failure. Chemotherapy-induced ovarian failure may decrease sexual desire and increase vaginal dryness. However, given that cancer faces women with a life-threatening condition, it is unlikely that these effects can be attributed only to hormonal changes [273]. Across studies, it appears that relationship happiness plays a more important role than physical factors in response to cancer treatment. years after breast cancer diagnosis, sexual activity decreased despite overall higher quality of life [277]. Specifically chemotherapy-induced ovarian failure, rather than a genital toxicity of chemotherapy, is responsible for these effects. These same authors developed a predictive model for sexual interest, sexual dysfunction, and sexual satisfaction after breast cancer in two very large independent groups of breast cancer survivors [279]. They found that the most important predictors of sexual health in sexually active cancer survivors were : absence of vaginal dryness, emotional well being, body image, quality of the relationship, and partner's sexual problems, accounting for 33% of the variance. 3. DIABETES In a systematic review of women with diabetes, reports of problematic desire, arousal, and orgasm experience vary widely from study to study and do not appear to have a simple correlation with degree of complication of their disease [280]. These authors speculated that difficulties with orgasm may be secondary to decreased sexual desire and arousability, rather than a primary problem with orgasmic function, per se. In the laboratory setting, neither subjective nor psychophysiological sexual arousal was found to differ between 24 women with diabetes mellitus type I and 10 control women [281]. However in the clinical setting, a large outpatient sample of 120 women attending a diabetes clinic, higher rates of overall sexual dysfunction were found compared to a normal control sample of 180 women [9], but a significant effect was found only for the complaint of decreased lubrication. Depression was found to be a significant predictor of these sexual complaints, and lower overall quality of marital relationship was also a factor in those women with sexual dysfunction [9, 282]. Across studies, there was evidence that psychological, as opposed to somatic, factors largely accounted for these sexual complaints in women with diabetes see Table 23. The fear of diminishing orgasm with hysterectomy has led to the development of either supracervical [274] or “nerve-sparing hysterectomy” [275]. The detailed neuroanatomy of autonomic fibers in the lateral aspects of the cardinal and uterosacral ligaments has recently been clarified and should enable preservation of genital sexual function whenever possible [276]. Nerve-sparing hysterectomy has been shown to improve rates of post-surgical incontinence, controlled studies examining effects on sexual function remain are beginning [269]. 2. BREAST CANCER Difficulties with sexual function following treatment for breast cancer are the most likely areas of distress to persist a year after diagnosis [277]. It appears that chemotherapy during treatment for breast cancer is responsible for most of the resulting sexual difficulties, such as loss of desire, trouble getting subjectively aroused, vaginal dryness, and pain with intercourse - see table 22. Twenty-eight percent of women who had undergone breast reconstruction or partial mastectomy without chemotherapy, versus 37% of women who received one of these surgeries with chemotherapy, met criteria for hypoactive sexual desire disorder [278]. In one of the largest longitudinal follow-up studies of 817 women 5-10 4. MULTIPLE SCLEROSIS Compared to the literature on men, relatively few empirical investigations into the sexual health of women with MS are available. Across investigations, there appears to be a significant amount of variability in the prevalence of sexual dysfunction in this group, and this is partially attributed to the failure to include control comparison groups. Recent data comparing women with MS to the general popula- 909 Table 22 Studies examining the role of breast cancer and its treatment in women’s sexual function and dysfunction. SD = sexual dysfunction; LOE = level of evidence 910 Table 23 Studies examining the role of diabetes in women’s sexual function and dysfunction. SD = sexual dysfunction; LOE = level of evidence. 911 Table 23 Studies examining the role of diabetes in women’s sexual function and dysfunction. SD = sexual dysfunction; LOE = level of evidence. 912 rediscovery that takes place some years following the injury. tion showed more difficulty masturbating and a lack of sensations or numbness - difficulties related to the nerve damage of MS [283]. Men and women as a group had higher levels of overall sexual dysfunction, and lower levels of sexual activity, relationship satisfaction, and sexual satisfaction than the general population. Face-to-face interviews of women with MS suggest more problematic sexual function with 73% of women reporting a sexual dysfunction compared to 39% of other chronic disease samples, and 12% of controls in an Italian sample of women [6]. These authors speculate that sexual dysfunction in women with MS is attributable to both physical (e.g., sphincteric dysfunction, fatigue, sensory loss) and psycho-social (e.g., depression, anxiety) factors [284]. In a qualitative study, Koch and colleagues found that sexuality was regarded as an important part of life in their sample, despite the acknowledgement of specific sexual difficulties and strongly advocate for health care professionals to reject the myths surrounding the “asexual” status of women with MS [285] - see Table 24. 5. BRAIN INJURY When brain injury is involved, Oddy [290] notes that the effects of the injury on sexual function may be attributable to direct neurological or endocrinological effects, from prescribed drugs, from psychological factors related to loss of confidence or motivation, and partner-related changes such as withdrawal. Past studies of sexual effects of stroke have suggested lesions in the right hemisphere to be more frequently associated with low desire and sexual dysfunction. However this was not the case in a recent series of 46 men and 16 women [291]. These authors found sexual hesitancy was common and due to both partners' fear of provoking another stroke and partner's dislike of the idea of “having sex with a sick person”. 6. CARDIAC DISEASE The literature suggests that women are treated less seriously and aggressively than men when presenting with symptoms of heart disease. However, statistics indicate that the number of female deaths surpasses the number of male deaths due to heart disease. With respect to sexual function, the Myocardial Infarction Onset Study group interviewed 1774 patients approximately one week after a myocardial infarction to understand possible triggers for the event, including sexual activity [292]. They found that the relative risk for having a myocardial infarction (MI) two hours after sexual intercourse was small and transient (2.9). Moreover, physical exercise decreased the risk of MI onset two hours after sexual activity from 3.0 to 1.2, for individuals who exercised 3 or more times/week. An effort has also been made to examine the resumption of sexual activity following MI. Hamilton and colleagues mailed questionnaires to 54 women and 110 men who survived an MI from a medical center in New England [293]. Of those who returned their questionnaires, 20 women and 42 men, all resumed sexual activity after the MI, with an average time to resume of 8.3 weeks. Thirty-nine percent reported that information regarding sexual activity from their health provider was either insufficient (15%) or not discussed at all (24%). Compared to men, women significantly reduce the frequency of sexual activity following the MI. 5. SPINAL CORD INJURY Problems with vaginal lubrication are common even in premenopausal women with spinal cord injury, since depending on the level of injury, the peripheral autonomic nervous system may not respond to central nervous system sexual arousal - see Table 25. In women with SCI, difficulties with orgasm are common, as are reports of unusual experiences, such as having a sensation of orgasm at the anatomical area where sensation begins to be present [286]. In a laboratory study comparing sexual arousal and orgasm in women with SCI to able-bodied women, only 44% of women with SCI, vs. 100% of able-bodied women, were able to reach orgasm in the laboratory; however, the experience of orgasm was the same in the two groups [287]. In a group of 85 SCI women, sexual dysfunction was reported to significantly increase post-injury, whereas importance of sex was unchanged [288]. Interestingly, there was an inverse relationship between sexual dysfunction and the importance of sex, such that women reporting higher levels of sexual dysfunction tended to place less importance on sex. Body satisfaction, which was higher than for eating disorder patients and comparable to volunteers, was not associated with sexual frequency or dysfunction. Tepper and colleagues conducted a qualitative study on the psychosocial, emotional, and relationship aspects of sexuality in women with SCI [289]. They described a sexual Westlake attempted to understand the sexual 913 Table 24. Studies examining the role of multiple sclerosis (MS) in women’s sexual function and dysfunction. Q = qualitative; SD = sexual dysfunction; LOE = level of evidence. 914 Table 25 Studies examining the role of spinal cord injury (SCI) in women’s sexual function and dysfunction. Q = qualitative; SD = sexual dysfunction; LOE = level of evidence. 915 concerns of patients and partners with advanced heart failure [294]. They found that dissatisfaction with the sexual relationship (55%) and loss of sexual interest (63%) were significant complaints among the partners of individuals with advanced heart failure. They advocate for more attention to the partners when providing counseling to individuals with heart failure - see Table 26. the context of women's sexuality. Recent large scale population-based studies find that well being plays a more important role than traditional markers of physical sexual arousal in predicting sexual distress [4], and low emotional satisfaction and happiness are associated with all categories of women's sexual dysfunction [2]. The relationship between well being and hormones has also received a significant amount of attention over the past ten years [22]. Whereas earlier studies may be criticized for using unvalidated measures of well being, even well-validated measures of well being, such as those employed in the Melbourne Women's Midlife Health Project fail to find associations of well being and hormone levels [72, 295]. Against this background of large prospective and cross sectional studies failing to find a correlation between endogenous levels of estrogen, androgen and well being, RCTs of supplementation have been conflicting. The addition of testosterone undecanoate to estrogenized women failed to find effects on well being [183]. The WHI study of CEE plus medroxyprogesterone to asymptomatic postmenopausal women failed to show a relationship between hormones and well being [235]. Recently, there was some evidence that transdermal testosterone improved well being in women with sexual dysfunction after bilateral oophorectomy (i.e. the women achieving high normal testosterone levels showing improvement on one of the two measures) [182]. IV. FACTORS ASSOCIATED WITH SEXUAL RESILIENCE Resiliency is a psychological attribute that describes the individual's ability to cope with significant adversity or stress in ways that are not only effective, but result in enhanced ability to confront and master future adversity. This is an important area to study because many of the chronic illnesses discussed in this section carry with them the potential to further impair physical health. Adversity has been studied in various groups of survivors to severe physical or psychological stressors. For example, women with ovarian cancer who were studied after they had been without treatment for two years reported excellent mental health and quality of life, despite ongoing physical difficulties such as sexual dysfunction [264]. Women with MS [35] and SCI [289] who were able to redefine their experience of sexuality due to physical limitation are further examples of resilience in the face of adversity. Such women were able to continue to enjoy satisfying sexual encounters because resilience enabled them to focus on new aspects of sexuality. Women with MS who showed problem-focused coping, focused on the positive, and those with better cognitive functioning had better sexual satisfaction and function [283]. With the advent of state-of-the-art treatments for even the most serious physical and psychological illnesses, research must begin to focus more on survivorship. In this way, the role of resilience as a contextual factor in women's sexual function will be clarified. Whereas hormone levels were not shown to play a key role in the Australian study, well being significantly increased from early to late/postmenopause, and this was significantly affected by life events such as having a partner, work satisfaction, and life hassles [296]. Having positive feelings for the partner has been shown to strongly positively influence sexual desire, responsivity, well being and protect against menopausal symptoms [33]. Similarly, the health of the emotional relationship with the partner during sexual activity was a robust indicator of sexual distress in the recent large population based study [4]. Taken together, the epidemiological literature plus the empirical literature on hormones, suggest that well being is an important contextual factor to be considered in women's sexual function. Moreover, it is likely much more robustly related to life events, than to hormones, and it affects women's sexual health more strongly than traditional physical markers of the human sexual response. V. GENERAL EMOTIONAL WELL BEING AND SEXUAL FUNCTION Well being, a similar psychological attribute that is considered to cover a broader range of affect than positive or negative mood, has also been studied in 916 Table 26 Studies examining the role of ischemic heart disease in women’s sexual function and dysfunction. LOE = level of evidence; MI = myocardial infarction. 917 loss of sexual interest are common complaints among partners of individuals with chronic heart failure, and deserve more attention by the health care provider. VI. SUMMARY Considering the role of context in women's sexual function is an essential component of assessment and treatment. Here we provided a brief review on the literature on (1) role of partner's sexual health, (2) role of various chronic illnesses, and (3) role of resilience and well being, in affecting women's sexuality. • The clinician must assess sexual function of the partner. • A partner's sexual health significantly affects a woman's sexual well being, sexual disability, and quality of life. The effects are complex. • When considering the role of physical illness in sexual function, the clinician must include a multidimensional assessment that considers : • Chronic illness may impact sexual function via physiological and/or psychological factors, making it important to consider both. - The role of biological factors that might impact sexual response VII. RECOMMENDATIONS - Effects of the chronic illness, such as fatigue or chronic pain • Treatment of the chronic illness itself can affect sexual function. - Psychological reactions to the illness that may reach clinically significant levels (e.g., a depressive episode) • It is difficult to differentiate the separate contributions - vascular, neurological, hormonal, and psychological to dysfunction associated with pelvic cancer. Results after nerve sparing surgery are encouraging. - The effects of treatment of chronic illness on sexual response - Mobility restrictions that may limit the range of sexual practices • It appears that chemotherapy induced ovarian failure during treatment for breast cancer is responsible for most of the resulting sexual difficulties. • For women who have faced significant physical or psychological adversity, encouragement of her resilience (through psychotherapy, support groups, education) may facilitate better long-term adjustment to the illness itself and to related sexual difficulties. • Studies on sexual function in women with diabetes are inconclusive, with laboratory studies failing to find significant differences in genital congestion between women with and without diabetes, whereas some clinical studies find significantly higher rates of sexual dysfunction in the former. Despite the presence of potentially relevant physical factors, it is clear psychological factors have more impact. • Sexual well being should be fostered by focusing on life events that promote emotional health. For the otherwise healthy woman, less attention should be placed on physical response, when addressing sexual distress. • Questionnaire and interview studies on women with multiple sclerosis suggest impairments in sexual desire, arousal and orgasm compared to healthy women M. CHILD SEXUAL ABUSE AND SEXUAL DYSFUNCTION • Laboratory and clinical investigations of women with spinal cord injury clarify preservation and impairment of sexual function. I. INTRODUCTION • Qualitative methodology in women with multiple sclerosis and spinal cord injury suggest that the experience of sexuality evolves over the course of their illness and is no longer focused on intercourse. Factors influencing the etiology of sexual dysfunction are multifaceted and often poorly understood. One area receiving increasing attention is the role that early sexual abuse plays in later sexual functio- • Dissatisfaction with the sexual relationship and 918 ning for women. Child sexual abuse (CSA) and sexual dysfunction both occur frequently and are usually not reported. While significant associations between CSA and HIV-risk behaviors [297, 298] have been documented, more understanding of many other sequelae including effects on sexual function and behaviours is needed. IV. CHILD SEXUAL ABUSE AND SEXUAL DYSFUNCTION The limitations in sampling and methods of the research make it difficult to understand how CSA influences sexual dysfunction. Most studies are level 2b or 4. The trauma of CSA may result in psychosocial disturbances that affect sexual function [307]. Because they were powerless to make their own decisions about sex as children or adolescents, women may not develop adequate sexual communication and decision-making needed to interact with sexual partners. II. THE DEFINITION OF CHILD SEXUAL ABUSE Definitions of CSA vary according to the types of sexual behavior included in the definition, the upper limit placed on the victim's age at the time the abuse occurred, and the criteria used to define the incident as abusive [299]. Wyatt [300, 301], initially defined CSA as sexual body contact prior to age 18 by someone of any age and relationship to the victim. Two additional exclusion criteria were used to distinguish CSA from exploratory sexual experimentation before age 12 or consensual sexual activity with peers [302, 303]. Incidents were considered to be sexual abuse if : (a) the age difference between the alleged perpetrator and victim was more than 5 years ; or (b) the age difference was less than 5 years, but the contact was not desired or was coercive. National and international definitions of CSA need to consider the age of legal consent to engage in sexual activities so that non-consensual incidents can be evaluated for their coercive and explorative effects. Sex can also become associated with pain and trauma, anxiety and thus, sexual dysfunction [308]. Flashbacks or intrusive thoughts of sexual abuse may compromise sexual function and enjoyment [308] V. ABUSE, ETHNICITY, CULTURE AND SEXUAL DYSFUNCTION Although race and ethnicity have not received adequate attention with regard to CSA [309], the sociocultural context in which CSA occurs influences initial reactions to the abuse, the effects of disclosure, and associated symptomatology [300, 306]. Epidemiological studies with female CSA survivors have been primarily limited to European American women [306]. Less is known about sexual dysfunction within various ethnic and cultural groups. III. THE TYPES AND PREVALENCE OF CHILD SEXUAL ABUSE Few differences in prevalence rates among African American, Latina, American Indian and European American women with histories of CSA have been documented [300-302]. Similarities in prevalence rates suggest that ethnic background is not a risk factor for CSA. However, the circumstances surrounding abuse incidents and how families respond to them can differ by ethnicity [309]. Researchers have confirmed that many more children are sexually abused than are reported to authorities [300, 304]. Wyatt and associates [303] reported contact abuse incidents ranging in severity from those that were less severe (fondling and frottage) to very severe (digital penetration and attempted or completed oral sex, anal sex, or rape). A commonly reported estimate of the prevalence of CSA in the United States is approximately 33% in community samples of girls under the age of 18 [303] and approximately 5% in boys under 18 years of age 14 [305]. Research examining the stability of prevalence rates suggests that the prevalence of CSA among girls has remained stable over time [303, 306]. The inclusion of a more comprehensive sampling of women of a variety of ethnic groups and nationalities is also necessary to understand issues pertaining to possible ethnic differences in sexual consequences of CSA. 919 In a nationally representative sample of 1,335 Swedish women, 12% of respondents had been sexually abused at least once in their life times - half of them abused more than once. Two-thirds of those abused had at least one sexual dysfunction compared to twofifths of non-sexually abused women. Importantly, the sexually abused women had a significantly higher number of sexual dysfunctions. The majority of types of sexual abuse were significantly associated with orgasmic dysfunction. When there had been vaginal penetration, genital manipulation, forced giving or receiving oral stimulation, there were lower levels of sexual interest. Additionally, forced giving of oral stimulation and genital manipulation were associated with a higher prevalence of vaginismus. In this study, no significant difference was found in levels of sexual function between those violently as opposed to non-violently abused [12]. VI. ASSOCIATION OF CSA AND ADOLESCENT SEXUAL FUNCTIONING Sexual abuse research has focused primarily on children and adult women. Less attention has been given to adolescent girls. Evidence suggests that psychological and biological processes of pubertal development may add increased stress to this phase of development [310]. Physical complaints of sexually abused girls and adolescents include genital abnormalities (e.g., discharge, bleeding, pruritis, skin lesions, and trauma), genital infections, sexually transmitted infections, recurrent urinary tract infections, abdominal pain, and pregnancy [310]. These symptoms and diseases may affect body image and sexual function [311]. However, these findings need to be replicated with more representative samples, in order to better understand how CSA might influence a cumulative history of sexual dysfunction beginning in adolescence [312]. Interpretations of these findings are inconsistent due to sampling limitations. Some investigators have found that childhood and adult sexual abuse (ASA) similarly disrupt sexual functioning. Others report that associations with CSA are different than those of ASA [316]. Becker, Skinner, Abel, and Treacy [317] noted that women who had experienced incest as children were likely to have orgasm dysfunction, but this did not occur for women who experienced only adult sexual assault. Additional research is needed with more representative samples and control groups of non- abused women VII. ASSOCIATION OF CSA AND SEXUAL FUNCTIONING IN ADULT WOMEN It is important to examine sexuality in the context of interpersonal functioning and to understand the relationship between CSA and long term individual and relationship adjustment [313]. Several studies have reported increased difficulties with sexual function and orgasm in women with past CSA, especially if the abuse involved incest and/or sexual penetration and force [313]. Multiple incidents of CSA also increased the chance of difficulty with desire, arousal and orgasm [314]. Much of the research on women's sexual dysfunction focuses on measures of sexual performance, examining symptoms, including low sexual desire or arousal, orgasmic dysfunction, and vaginismus. However, a focus on symptoms alone, without an examination of their context as well as other etiological factors, reveals only limited information about the possible effects of sexual abuse on sexual functioning. It is recommended that future studies also examine the context of the wanted sexual function. Other links between CSA and sexual dysfunction have been noted. Laumann, Paik, and Rosen [2] reported associations between sexual dysfunction and prior negative sexual experiences, including CSA. Women's sexual victimization in childhood was associated with difficulties in becoming aroused and lubricated. In summary, the association of CSA with sexual dysfunction is more pronounced for women who experience severe abuse (i.e., penetration, force, incest, multiple incidents), report family dysfunction or other types of child abuse, or who experience revictimization in adulthood. Other emotional problems or stressors can also increase the probability of sexual dysfunction. These findings highlight the importance of examining the context of a person's past and present sexual experiences when examining the influence of CSA. In a prospective study of African American women with documented histories of CSA, those who experienced revictimization in adulthood reported more painful intercourse, vaginal infections, and STIs than those who experienced only CSA [315]. 920 X. TREATMENT FOR SEXUAL DYSFUNCTION IN THE CONTEXT OF PAST ABUSE VIII. CSA AND RELATIONSHIP SATISFACTION Compared to women without a CSA history, CSA survivors face greater difficulties in their relationships, including less relationship satisfaction, more high risk sexual behavior, more intrusive thoughts and partner violence [312]. Women who reported multiple types of childhood abuse described greater fears of intimacy, and intrusive experiences than those who experienced no abuse and those who experienced either physical or sexual abuse alone [318]. · Treatment for sexual trauma should be addressed before treatment for sexual dysfunction can begin. · Therapy should help women understand any possible connections between past and current sexual functioning, particularly re feelings of trust and being sexually vulnerable. · Important aspects of therapy include : • Encouragement that women can be in control of their sexual encounters. In summary, CSA can have lasting effects in the area of adult sexual relationships. • Learning to mentally and physically relax prior to receiving sexual stimulation. • Recognition that women need only engage in encounters with which they are fully comfortable. IX. ASSESSMENT OF SEXUAL DYSFUNCTION IN THE WOMAN WHO DISCLOSES CSA • Help to develop verbal and non-verbal communication with sexual partners to limit further sexual stimulation when feeling overwhelmed, “numb” or fearful. • Assessment of recovery from the abuse (with or without past therapy) : - history of recurrent depression - history of substance abuse, self-harm - history of promiscuity - unable to trust especially persons of the same gender as the perpetrator - exaggerated need for control - exaggerated need to please (and inability to say no) • Assistance to develop relationships where there is a healthy balance of power. • When relevant, explanation of the reflexive (automatic) physiological genital responding that sometimes occurs during abusive/coercive sex. It is clear that when sexual dysfunction has its roots in childhood trauma, a pharmacological intervention is likely to prove ineffective in resolving sexual symptoms. A more extensive exploration and confrontation of the psychological, emotional, and relational issues that impact women's sexuality, is needed. Berman and associates examined the efficacy of sildenafil (Viagra), a drug used to treat arousal disorders in men, for women with and without a history of CSA seeking treatment for sexual dysfunction [319]. This drug was effective in increasing sexual arousal (including lubrication, genital sensation, satisfaction with intercourse, and orgasm) for women who had no history of CSA, but not for women with those histories. These findings illustrate the importance of obtaining complete sexual histories when treating female sexual dysfunction with medications. • When recovery is incomplete further assessment of the abuse is necessary. However, its timing is important - therapy for the abuse should follow any detailed questioning : - circumstances of the abuse including woman's age and perpetrator's age - what sexual behaviours occurred - if there were forces or threats made - if there was reflexive genital responding and if so, did the perpetrator compound her distress by stating such a response meant she “enjoyed or wanted it”. Does she understand now why that can happen ? - if she reported the incident to anyone and that person's reaction - her knowledge of the whereabouts of the perpetrator currently. 921 dures, recently termed “genital cutting”, are seen and performed in many other parts of the world, including Europe and the United States. It is recommended that health practitioners understand the different types of female circumcision and their sexual complications, as well as those that are medical and obstetric. However, the strong recommendation is to address these issues with sensitivity and awareness of the historical and cultural beliefs that are enmeshed, such that effective appropriate interventions can be made. XI. RELEVANCE OF SEXUAL ABUSE TO THE ASSESSMENT AND MANAGEMENT OF SEXUAL • Abuse is common and enquiry re its occurrence must be a routine part of the assessment of women's sexual dysfunction. • Given internal pelvic examinations can provoke emotions associated with the abuse, these should not be considered simply “routine” for all women with sexual complaints, but rather there must be a reason for such an examination and its nature and purpose explained to the woman ahead of time see page 871. II. FEMALE GENITAL ANATOMY The parts of the external female genitalia involved in female circumcision are : • The evidence is that sexual dysfunctions, especially orgasm dysfunction, is correlated with a past history of sexual abuse. 1) Mons Pubis : the area where the labia majora join together at the top of the vulva. • Given poorer general relationship satisfaction is also associated with past sexual abuse and women's sexual function is closely linked to relationship satisfaction, sexual sequelae of abuse can be severe. 2) Perineum : the skin between the anus and the opening of the vagina. 3) Labia majora : two easily seen elliptical folds of skin extending between the pubis and the perineum. • Once the history of sexual abuse is elicited, there must then be an assessment of the woman's recovery. 4) Labia minora : two smaller folds of skin beneath the labia majora. They extend from the perineum to meet and surround the clitoris. • When recovery is incomplete, it is necessary to advise that the abuse itself is addressed rather than moving onto any definitive treatment for sexual dysfunction per se [320]. 5) Clitoris : structure similar to the penis but much smaller, located about one-half inch above the urethral opening at the point where the labia minora meet. Clitoral tissue is extensive - the visible, palpable part being less than 10%. It extends under the pubic bones and connects with similar tissue around the vaginal opening under the thin superficial perineal muscles - “bulbs of the clitoris”. N. FEMALE GENITAL MUTILATION AND SEXUAL DYSFUNCTION I. INTRODUCTION III. SURGICAL PROCEDURES AND SEXUAL FUNCTIONING More than 130 million women and girls worldwide have experienced “excision”, commonly known as female circumcision. Surgical alteration of girls and women's genitalia has been performed for more than 4,000 years [321]. It is estimated nearly 2 million women and girls continue to be excised yearly [321]. Female circumcision is practiced in at least 26 African countries with some regularity [321]. With the current increase in international travel these proce- Literature on sexual functioning after female circumcision is limited and most of what is to follow has been accumulated from clinical practice and group discussions between the author and girls and women who have been excised. Dyspareunia, orgasmic delay and lack of orgasm are not uncommon [322]. One study found approximately half the women 922 reported lack of sexual desire. Similarly, half reported lack of sexual pleasure and 60% lack of orgasm [323]. The imposed infertility from infection of these procedures can indirectly affect the woman's sexual functioning as the psychosocial consequences of infertility in communities practicing genital circumcision, can be extreme. Moreover, emotional distress and physical pain during sexual stimulation and intercourse diminishes enjoyment for the man also, impairing the intimacy of their relationship and again indirectly, therefore reducing the woman's sexual function. The types of female circumcision are [321, 324] : 4. TYPE IV : PRICKING, PIERCING OR INCISING THE CLITORIS AND OR LABIA. Depending on the extent of the excision the effect of Type IV excisions may be marginal to extreme. Hypersensitivity to direct clitoral contact may lead to dyspareunia and/or decrease in sexual desire to avoid the pain associated with vaginal penetration. Procedures performed in type IV circumcisions include a) stretching of the clitoris and/or labia, b) cauterizing the clitoris and/or surrounding tissue, c) scraping the tissue surrounding the vaginal opening (angurya cuts), d) cutting into the vagina (gishiri cuts) and e) inserting corrosive substances or herbs into the vagina to tighten or narrow it. 1. TYPE I : EXCISION OF ALL OR PART OF THE CLITORIS AND ITS PREPUCE OR SKIN. These procedures are usually associated with less painful intercourse but can be associated with psychological problems that affect sexual functioning. Removal of the visible part of the clitoris, its covering (frenulum below and prepuce above formed by the labia minora) and perhaps its suspensory ligament, will also involve cutting its blood supply (branch of the internal pudendal artery) and innervation (branch of the pudendal nerve). This can lead to chronic referred pain over the lower back and groin. Dyspareunia with diminished or absent arousal, orgasm and sexual satisfaction can occur. Type I is performed 80% of the time. Type III is performed 15% of the time. IV. REASONS GIVEN FOR FEMALE CIRCUMCISION/FEMALE GENITAL MUTILATION 2. TYPE II : EXCISION OF THE CLITORIS WITH PARTIAL OR TOTAL REMOVAL OF BOTH LABIA Female circumcision is commonly performed prior to puberty but can be done as early as 7 days after birth [326]. Female circumcision can be performed more than once especially in some women who request re-suturing of the vagina after childbirth. The most common reasons given for this procedure, are to [327] : MINORA. When the labia minora have been partially or totally removed along with the clitoris additional blood vessels (pudendal branches from the femoral artery and vein) and nerves (branches of the ilioinguinal, pudendal and genito-femoral) are cut. Referred pain is to the vagina. This can heighten or exaggerate the female sexual dysfunction described with type I. 1) maintain chastity and virginity until marriage 2) maintain fidelity during marriage (3) increase the man's sexual pleasure 3. TYPE III : EXCISION OF ALL EXTERNAL GENITALIA, CLOSURE OF THE VAGINAL OPE- 4) heighten the woman's sexual desire. 5) help keep the genitalia clean and pleasing to the eye. NING EXCEPT FOR A MATCH TIP SIZE AREA FOR URINE AND BLOOD TO ESCAPE. Removal of all external genitalia is accomplished with this excision. Not only is there a greater chance for more pronounced sexual dysfunction but placement of sutures and binding the legs together leads to higher rates of infection and known findings of nerve entrapment and scarring. 6) follow the cultural tradition of initiating girls into womanhood 7) follow religious tradition 8) enhance fertility and child survival Less common myths are: men prefer circumcised women ; a man can get sick or even die if his penis comes into contact with an uncircumcised woman's genitals ; circumcision prevents cancer; men cannot This procedure may result in dyspareunia and/or vaginismus. Women may report low sexual desire due to fear of pain upon penetration. 923 match an uncircumcised woman's unbridled sex drive; circumcision prevents masturbation ; and without circumcision the clitoris may grow to an enormous size and hang between the woman's legs. VII. ASSESSMENT OF SEXUAL FUNCTION IN WOMEN WHO HAVE SURVIVED “GENITAL CUTTING” Assessing the sexual health of girls and women should be carefully and respectfully conducted. Women have reported feeling betrayed by mothers, husbands and other family members when forced to undergo excision [326]. “Routine examination” is rarely an appropriate concept for women with these histories - rather physicians must be aware that such procedures may trigger flashbacks, especially in those suffering from post-traumatic stress disorder associated with the genital cutting Psychotherapy is recommended to help those who report traumatic experiences with female circumcision. Therapy should include assessment of any sexual dysfunction. While not all women report sexual problems as a result of female circumcision, it is important to offer them an opportunity to discuss feelings and learn skills to increase self-esteem and sexual satisfaction. Caution is recommended to remember that many of these women may well be well adjusted and have no sexual complaints [328]. V. IMMEDIATE EFFECTS OF FEMALE CIRCUMCISION/FEMALE GENITAL MUTILATION Immediate effects of female circumcision are severe. Pain, bleeding and shock may occur. It is ironic that in some cultures circumcision is performed on the 7th day of birth to “lessen” the amount of pain. Unfortunately there is tremendous pain and occasionally bleeding and shock leading to death. As the site of surgery heals swelling (congestion) and infection are common since the technique is carried out with non-sterile instruments and the circumcised person may be forced to remain with legs bound together for 40 days. Before history and physical examination are performed, both male and female physicians should ensure that trust and rapport is well established. Often but not always, the presence of a female chaperone is helpful. Initially a discussion defining sexual dysfunction and how it can affect relationships and sexual satisfaction is necessary. The following question can be asked, “Do you have any sexual concerns you need to discuss ?” During the physical examination care should be taken to thoroughly inspect and palpate the genital and pelvic anatomy. This should include an anorectal exam, demonstration of control of vaginal muscles and strength of pelvic floor muscles. The type of female circumcision should be pinpointed. The examiner should note the amount and site of pain. Pain can be graded on the cardinal score of zero to ten with zero for no pain and ten for the worst pain. Each site of pain should be noted anatomically and a score placed on its location. Any consideration for sex therapy should include the continuum of pain a woman describes. A woman's partner and family may need to be included in counseling sessions in order to educate families about the effects of female circumcision on the woman's psychological well being and physical health. Additional treatment for sexual dysfunction may range from recommending vaginal lubricants and pelvic floor strengthening exercises to surgical correction and should be individualized. VI. LONG TERM EFFECTS OF FEMALE CIRCUMCISION/FEMALE GENITAL MUTILATION The combination of scar tissue, trapped nerves, compromised blood supply and formation of neuromas increase the chance of continued pain at the point of circumcision, the surrounding area and the abdomen. Although the underlying pathophysiology is poorly understood dyspareunia is an unwanted side effect of female circumcision. Since pain is an unpleasant experience it is also an emotional experience. There is no direct relationship between the amount of tissue damage and the degree of pain perceived. Factors such as : 1) the amount of distress experienced as a result of the excision ; 2) traumatic memories ; 3) family dysfunction ; 4) financial status ; 5) a history of substance abuse and 6) relationship problems, all influence perceptions of pain and sexual dysfunction. Even with similar procedures and stimuli individuals will have different perceptions of the amount of pain. 924 O. MANAGEMENT OF ANTIDEPRESSANT-ASSOCIATED SEXUAL DYSFUNCTION VIII. FUTURE RECOMMENDATIONS 1. Ways to facilitate change of beliefs within the communities practising excision are urgently needed. Adequate systematic studies of medication (antidepressant medication in particular) associated sexual dysfunction in women, have not published. Clinically, the most common concerns are with selective serotonin reuptake inhibitors reducing sexual responsiveness. This is thought to be possibly due to increasing the serotonergic tone, thereby reducing dopamine mediated activation of sexual response, and augmenting the descending inhibitory serotonergic pathways. Despite apparent benefit of the 5HT1A agonist buspirone, and the dopaminergic agonist amantadine in uncontrolled studies, neither drug was statistically superior to placebo in a twomonth RCT [329]. Sexual pleasure, psychological arousal, overall sexual function was reviewed, as well as sexual interest/desire, lubrication and orgasm. 2. Laws prohibiting female circumcision need to be enforced. 3. Further investigation is necessary to fully understand all circumstances surrounding this spectrum of “surgeries”, especially the claim of genital rejuvenation and increased sexual pleasure. 4. Girls and women who have undergone genital circumcision should be encouraged to seek out support groups for FGC survivors. They should be informed about the surgical options for repair including the release any constricting sutures, reconstruction of the vagina and improving or correcting any blockage of urine or menstrual blood. Again, it is recommended to be aware that such a surgical intervention may bring back acute awareness of the original trauma. A case series of 106 women treated in a nonrandomized manner with either moclobemide, paroxetine, sertraline or venlafaxine, were followed for sexual complications [330]. There was somewhat less reduction of desire/interest for those on moclobemide and to a lesser extent for those on venlafaxine and there was less reduction of arousal with these two drugs. Lubrication difficulties were rare only with moclobemide and interestingly, no women taking moclobemide reported orgasm difficulties. 5. Psychotherapy should be available and outcome studies conducted. 6. Aside from laws prohibiting female circumcision under the age of 18 in most countries, on an ethical basis, excision cannot be condoned. IX. CONCLUSION A randomized controlled trial of augmentation therapy with placebo, mirtazapine, yohimbine or olanzapine for 6 weeks given to women with fluoxiteneassociated sexual dysfunction, did not support the previous uncontrolled reports of efficacy with these agents in women [331]. It is recommended that health practitioners do not take a judgmental role. There needs to be close liaison between Sexual Medicine, Primary Care, Pediatrics, Obstetrics, Psychiatry and Psychology and importantly, the immigrant communities when women are being seen in western countries. Although numerous open label studies suggested bupropion combined with SSRIs ameliorated the SSRI-induced sexual dysfunction, a placebo-controlled bupropion add-on study of SSRI-associated sexual dysfunction showed no significant difference compared to placebo. It is of note that the dose of bupropion was fixed at 150 mg without any titration [332]. It is highly recommended that further randomized controlled studies are done given the high prevalence of sexual dysfunction associated with SSRIs and the frequent noncompliance that ensues with subsequent risk for relapse/recurrence of major depressive disorder. The challenge to change attitudes is immense and must continue as a major focus of human rights and other international non-governmental organizations. It is important to always be aware that even for those women who have relocated to the west, these seemingly abhorrent practices may, nevertheless, serve as a confirmation of their cultural identity. For some, it may be extremely important to preserve their traditions and cultures [328]. 925 var pain syndromes. This task force coined the term “vulvodynia” as chronic vulvar discomfort, characterized by the patient's complaint of burning (and sometimes stinging, irritation or rawness) in the vulvar area [336]. The term vulvodynia (the symptom) is often loosely used as a somewhat composite “diagnosis” covering several disorders, all of which result in chronic vulvar pain ; VVS, dysesthetic vulvodynia, vulvar dermatosis, cyclic vulvovaginitis, vulvar papillomatosis [337]. P. SEXUAL PAIN AND ITS MANAGEMENT I. INTRODUCTION Treatment for sexual pain disorders in the healing professions has always been a tricky matter. This is well-illustrated by a comment made by Robert Latou Dickinson in 1933 : At the 1999 World Congress of the ISSVD a new classification system for vulvar dysesthesia was proposed, namely a division into two broad categories : (1) generalized vulvar dysesthesia, (2) localized vulvar dysesthesia - vestibulodynia, clitorodynia and other. This new classification is based on location of pain (recognizing, that we know little about the etiology of pain in vulvodynia), in contrast the initial classification system focused on possible etiologies. However, as of June 2003 this new classification system has not been published in the peer-reviewed literature. “The surgeon thinks of difficult coitus in terms of a knife passed through muscles in spasm; the psychiatrist thinks of dyspareunia as a mental knot to be disentangled by analysis; the gynecologist who is weary of patching - poor and late patching - begins to think in terms of prevention through routine premarital examination and instruction” [333]. This section on the various aspects of sexual pain will review pathophysiology, psychopathology, treatments, prognostic factors but interestingly there are no studies on prevention. Everyone who regularly encounters the complaint of dyspareunia knows that women are inclined to continue with coitus, if necessary, with their teeth tightly clenched. The repercussions on the woman sexually and emotionally plus the distancing and misunderstanding between the two partners can make the treatment of sexual pain disorders difficult and frustrating for patients and clinicians. This review highlights the clinical presentation of two categories of sexual pain disorders, dyspareunia and vaginismus. As discussed earlier in this chapter, the ICD-10, and the DSM IV view sexual dysfunction as involving either psychological or somatic components or a combination, suggesting these are separate entities and that etiologies are usually known [56, 57]. However, sexual function is a supreme example of the mandatory blending of mind and body. Moreover the precise etiology of dysfunction is often unclear. Frequently, sexual pain is or becomes associated with lack of subjective arousal (and orgasm) and lack of desire/interest. Reduced genital congestion is frequently reported but is as yet not scientifically documented [78]. Whereas a lack of sexual arousal is one certain etiological factor, others are currently extremely unclear. We therefore do not recommend the specification of a biological or psychological etiology. 1. TERMINOLOGY Vulvar vestibulitis syndrome (VVS) is thought to account for the vast majority of chronic dyspareunia currently identified in some 3 -20% of nationally representative community studies [1, 2, 69]. The syndrome includes painful penile-vaginal intercourse or pain upon touching the vulvar vestibule and signs limited to variable vestibular erythema. Interestingly, hyperesthesia of the vulva, which features prominently in women with VVS, was a welldescribed entity in American and European gynecological textbooks more than 100 years ago [334, 335]. 2. OVERLAP OF PAIN SYNDROMES Current diagnostic systems also rely heavily on the sexual response cycle. However, the categories of pain disorders, vaginismus and dyspareunia are not part of the sexual response cycle. Also, the assumption that dyspareunia and vaginismus are distinct types of sexual pain disorders, have recently been challenged [338-342]. Research has demonstrated persistent problems with the sensitivity and specificity of the differential diagnosis of these two pheno- Surprisingly, despite early detailed reports, chronic vulvar dysesthesia disappeared to a large extent from the medical literature until the early 1980s. In 1982 the International Society for the Study of Vulvar Disease (ISSVD) formed a task force to survey vul- 926 mena. Both complaints may comprise, to a smaller or larger extent : 3. SEXUAL PAIN AND EVIDENCE BASED 1. Problems with muscle tension (voluntary, involuntary, limited to vaginal sphincter, or extending to pelvic floor, adductor muscles, back, jaws, or entire body) ; The Oxford system of levels of evidence unfortunately, is poorly adapted for this literature. There are very few empirical studies and the overall quality of evidence is poor. REPORTING 2. Fear of sexual pain (either specifically associated with genital touching/intercourse or more generalized fear of pain), or fear of intercourse for reasons other than pain ; The evidence that does exist is usually linked to one laboratory or investigator and has rarely, if ever, been independently replicated. By definition, therefore, most of the evidence is level 2b or below. 3. Propensity for behavioral approach or avoidance. Despite painful experiences with genital touching/ intercourse, a subgroup of women continues to be receptive to sexual partner initiatives or to self-initiate sexual interaction. Avoidance of opportunity and/or avoidance specifically of touch between the labia minora is characteristic of others. Q. NEUROBIOLOGY OF THE PELVIS A basic understanding of the neurobiology of the pelvic floor is paramount to gain further insight into the pathophysiology of urogenital disorders (which are characterized by disturbances of sensation and motility) and to develop effective clinical management strategies for patients presenting with these syndromes [343]. So, for example, complaints of pain upon genital touching, superficially located at the vaginal introitus during sexual activity, sometimes associated with other types of vulvar/vaginal/pelvic pressure (e.g., sitting, riding horse or bicycle, wearing tight trousers), are typical of VVS. However the above phenomena typical of “vaginismus”, may also be present. Over the last 15 years the basic neurobiology of the pelvic floor, despite its complexity, has come to be a reasonably well-developed discipline owing to an increasingly refined knowledge of principles pertaining to the neuroanatomy and neurochemistry of pelvic functions [344]. Despite the above, in this chapter, the independent existence of dyspareunia, VVS and vaginismus is a priori accepted to allow the use of the existent scientific literature based on this nosological distinction. For the present review in the etiology of sexual pain disorders, dyspareunia is defined as: recurrent or persistent genital pain associated with sexual intercourse [64]. It can be subdivided into deep and superficial pain. Superficial (introital) pain, dyspareunia may either be or not be identified as VVS. This section provides a detailed description of the female external reproductive system and pelvic floor musculature. It also contains a brief overview of the current knowledge of the relevant neurochemical basis for regulatory functions and sensory processing. Vaginismus has been defined as recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal penetration, which causes personal distress. As knowledge of etiology and treatment of sexual pain disorders advances, these definitions are being modified. An international consensus committee recently recommended the following definition [64]. It is important to note that the summary attempts to derive as much information as possible from investigations involving humans although some generalizations are necessarily taken from animal studies recognizing that much research in this field is in its infancy. Many of the animal studies concerned with the characterization of the autonomic outflow to the pelvis (unless they were specifically designed to assess the female reproductive tract) have primarily been conducted in male animals. The persistent or recurrent difficulties of the woman to allow vaginal entry of the penis, a finger, and/or any object, despite the woman's expressed wish to do so. There is variable (phobic) avoidance, involuntary pelvic muscle contraction and anticipation/fear/ experience of pain. Structural or other physical abnormalities must be ruled out/addressed. This caveat is important since there is some evidence to suggest that pelvic floor and perineal innervation may differ between men and women [345]. 927 hypogastric plexus (presacral nerve), hypogastric plexus (hypogastric nerve), inferior hypogastric plexus (pelvic plexus) and pelvic splanchnic nerve (pelvic nerve). I. NEUROANATOMY OF THE PELVIS AND PELVIC FLOOR The pelvis and pelvic floor are innervated by both divisions of the autonomic nervous system, the sympathetic and parasympathetic divisions, as well as by the somatic motor and sensory nervous systems. In a broad anatomical view, dual projections from the thoracolumbar and sacral segments of the spinal cord carry out this innervation, converging primarily into discrete peripheral neuronal plexuses before distributing nerve fibers throughout the pelvis (Figure 6). Interactive neuronal pathways routing from higher origins in the brain through the spinal cord add to the complexity of neuronal regulation in the pelvis. While it is important to appreciate the influence of supraspinal centres in the coordination of pelvic organ activities, it is beyond the scope of this review to discuss these interactions in further detail [346-352]. 1. THE INFERIOR HYPOGASTRIC PLEXUS Within the pelvis, the inferior hypogastric plexus is regarded to be the major neuronal integrative center. Neuroanatomical studies have confirmed its retroperitoneal location adjacent to each lateral aspect of the rectum, with interconnections between the left and right inferior hypogastric plexuses at the posterior aspect of the rectum [355-357]. It innervates multiple pelvic organs, including the urinary bladder, proximal urethra, distal ureter, rectum and internal anal sphincter, as well as genital and reproductive tract structures [358]. The anterior part of the inferior hypogastric plexus, associated with the distal extent of the hypogastric plexus (hypogastric nerve), is referred to as the paracervical ganglia. These are situated in the parametrium lateral to the cervix and the upper part of the vagina, and distribute nerve fibers to the corpora cavernosa of the clitoris, vagina and periurethral tissues [359]. The nomenclature of the various plexuses, ganglia and nerves in the pelvic cavity is varied and sometimes confusing presenting designations from both Nomina Anatomica and clinical usage [353,354]. In this review we have used the anatomical nomenclature, the clinical usage is given in brackets : superior Neuronal input to the inferior hypogastric plexuses involves sympathetic and parasympathetic systems. Sympathetic nerves originate in the thoracolumbar segments of the spinal cord (T10-L1) and condense into the superior hypogastric plexus located just inferior to the aortic bifurcation. Preganglionic efferents originate largely in the intermediolateral cell column whereas afferents have their cell bodies located in dorsal root ganglia of these segments. Nerve fibers project from the superior hypogastric plexus as paired hypogastric plexuses (hypogastric nerves) and fuse distally before diverging bilaterally into branches destined for the inferior hypogastric plexuses. Additional sympathetic innervation to genitourinary organs may involve preganglionic nerves which synapse on postganglionic nerves originating in sympathetic chain ganglia; these postganglionic nerves join sacral nerves and course to their destinations via pelvic somatic neuronal pathways (see description below) [360]. Parasympathetic preganglionic nerve efferents are thought to arise from cell bodies of the sacral parasympathetic nucleus located in the intermediolateral gray matter of the sacral spinal conus (S2-S4) and fuse as the pelvic splanchnic nerve before entering the inferior hypogastric plexus [361, 362]. Parasympathetic afferents have cell bodies located in the S2-S4 dorsal root ganglia and course also within the pelvic splanchnic Figure 6 : The neuroanatomy of the pelvis and the pelvic floor 928 nerve runs medial to the internal pudendal vessels along the lateral wall of the ischiorectal fossa dorsal to the sacrospinous ligament. The pudendal nerve divides into upper and lower trunks [366]. The lower trunk of the pudendal nerve gives rise to the inferior rectal nerve innervating the external anal sphincter and perianal skin. The dorsal nerve of the clitoris is derived from the upper trunk of the pudendal nerve. The clitoral and perineal neurovascular bundles are paired terminations of the pudendal neurovascular bundles. They arise at the pelvic sidewall. The clitoral neurovascular bundle ascends along the ischiopubic ramus to meet the neurovascular bundle from the other side close to the midline. Where the crura join to become the joined corpora (the body of the clitoris) the clitoral neurovascular bundles pass to the superior surface of the clitoral body to pass along that surface, supplying the clitoris but also largely passing as an intact large neural trunk into the clitoral glans. The perineal neurovascular bundle supplies the urethra and bulbs and is seen passing under the pubic arch to gain access to this area. These neurovascular bundles are very large, visible to the naked eye and the nerves are 2mm in diameter even in the infant. nerve. In addition to its parasympathetic efferent and afferent component the pelvic splanchnic nerve also receives postganglionic axons from the caudal sympathetic chain ganglia [90]. 2. PELVIC AUTONOMIC INNERVATION A distinctive distribution of pelvic autonomic innervation is recognized at the urogenital organ level. In women it involves inferior hypogastric plexus projections deriving primarily from the paracervical ganglia part of the plexus. Conspicuous nerve trunks run in the adventitia of the vagina parallel to its long axis, sending off anterior branches that course to the clitoris and periurethral tissues and local branches which enter the vaginal smooth muscle walls [354, 363]. A network of nerve fibers tends to follow vascular distributions and conspicuously terminates at the junction between the subepithelial connective tissue and the vaginal epithelium as well as within the epithelium. Nerve density is observed to be greater in the distal vagina compared with proximal regions [363]. The exact course of the nerves piercing the urogenital diaphragm to supply the vulvar tissues which engorge with sexual arousal is currently being delineated. The cavernosal or autonomic neural anatomy is microscopic and difficult to define consistently. It appears to be a network of nerves rather than discrete nerves. The remaining branch of the pudendal nerve, the perineal nerve, arises either from the upper or lower trunk or both trunks and provides innervation to the ischiocavernous, bulbocavernous and superficial transverse perineal muscles and the striated urethral sphincter and labial skin [366]. Many well-regarded anatomical texts have described that the pelvic floor muscles receive a dual innervation by the pudendal nerve and direct branches of the third and fourth sacral motor nerve roots [370-372]. However, a recent study in female cadavers found that a nerve directly originating from sacral foramina S3 to S5 crosses the superior surface of the pelvic floor to innervate the three levator ani muscles: iliococcygeal, pubococcygeal and puborectal muscles [366]. No pudendal nerve branch that innervated the levator ani muscles could be identified in this study. Branches of S4-S5 nerve roots forming the coccygeal plexus distribute to perineal, perianal, and scrotal (or labial) skin [369]. 3. SOMATIC INNERVATION Somatic efferent and afferent innervation to the pelvis is generally understood to involve the sacral nerve roots (S2-S4) and their ramifications. Somatic efferents arise within Onuf's nucleus situated in the ventral horn of the S2-S4 spinal conus, and afferents reach the dorsal horn with their cell bodies in dorsal root ganglia of these segments [364]. Central projections of somatic afferents overlap with pelvic nerve afferents within the spinal cord, which theoretically allows coordination of somatic and visceral motor activity [360]. The sacral nerve roots emerge from the spinal cord forming the sacral plexus, from which the pudendal nerve diverges (S2-S4, with the S3 segment providing the largest contribution) along with the sciatic nerve between an initial division of sacral nerves and a subsequent division of fibers that intermingle with autonomic pelvic nerves coursing to the inferior hypogastric plexus [365-369]. The pudendal nerve also receives postganglionic axons from the caudal sympathetic chain ganglia. In general, the pudendal 4. INNERVATION OF THE VULVAR AND VAGINAL AREA - CLINICAL RELEVANCE Most studies on vulvar/vaginal innervation have been derived from animal studies [343, 373]. Compared to other areas of neuroscience little is known about the functional neural correlates that signal the 929 wide range of sensations from the vulvar and vaginal area ranging from pleasure to pain. The vulva is densely innervated by branches of the pudendal nerves (somatic nerves), conveying information about gentle and intense mechanical stimulation to the sacral spinal cord (S2-S4). The vagina is innervated by the pelvic nerves (parasympathetic nerves). The cervix and adjacent fornix region of the vagina are innervated more densely than the rest of the vagina by the pelvic and hypogastric nerves. Recent evidence showing that in addition the vagus may innervate all components of the female reproductive tract may be important [374]. Information arriving from the vulva, vagina and cervix is conveyed to widespread regions of the CNS, implying that stimulation of these regions can affect a wide range of physiological and perceptual functions [375-378]. Fibers innervating the vagina are activated by both gentle and intense mechanical stimulation, including noxious stimuli [375, 379]. Mechanical probing (non-noxious stimuli) of the vagina and/or cervix has produced antinociceptive effects in rats and analgesia in women [380, 381]. The urogenital sinus of the embryo differentiates into the adult urachus, bladder, urethra and vestibule, which in the adult comprises a shallow funnel of endodermal origin, sandwiched in between the (ectodermally derived) vulva and vagina proper [382-385]. The human vulvar vestibule contains free nerve endings but has no specialized nerve endings such as Meissners or Pacinian corpuscles [386]. The first survey of the innervation pattern in the human vagina using a pan-axonal marker was published in 1995 [363]. Free intraepithelial nerve endings were only detected in the introitus vaginae region. These very superficial free nerve endings are considered to be nociceptive or thermoceptive [387]. Interestingly, two independent studies reported vestibular neural hyperplasia in women with vulvodynia, which might provide a morphological explanation for the vestibular hyperalgesia reported by these patients [384, 388]. but it also represents a critical integrative site for the neurochemical influences operative in the pelvis [364, 389, 390]. The structure contains multiple subpopulations of cells, defined by their putative neurotransmitter contents, and displays a highly specialized synaptic organization and system of signal processing. For example, while cholinergic preganglionic neurons provide a primary excitatory input to cholinergic postganglionics, postganglionic nicotinic receptors can provide feedback inhibition on preganglionic acetylcholine release. Similarly, noradrenergic sympathetic fibers synapsing on cholinergic postganglionic neurons or interneurons in the inferior hypogastric plexus impedes cholinergic synaptic transmission [389]. In fact, neuropeptides, purines, kinins, monoamines, and amino acids, as well as local factors such as prejunctional muscarinic receptors and non-neural endothelins, may all serve as cotransmitters or neuronal modulators of classical neurotransmitter (acetylcholine and norepinephrine) release. A major sensory role for urothelially released ATP acting via P2X3 receptors on a subpopulation of pelvic afferent fibers has recently been documented in P2X3 knockout mice [391]. 1. GENITAL ORGAN BLOOD ENGORGEMENT Clitoral and vaginal vasocongestion is generally associated with parasympathetic vasodilator mechanisms, among which acetylcholine, VIP and nitric oxide appear to be contributing neurotransmitters [8, 82]. Flaccid genital organ states appear to be tonically governed by adrenergic and possibly peptidergic sympathetic mechanisms [392]. It is contended that parasympathetic mechanisms also account for vaginal fluid transudation, which accompanies vaginal vasodilatation, and that neuropeptides are primary candidates for this regulatory function [390, 393, 394]. Somatic nerves also exert a significant role in activating bulbospongiosus and ischiocavernosus muscles as well as other muscles of the pelvic floor. Contraction of these perivaginal muscles during sexual stimulation contributes to intravaginal pressure effects [394]. II. NEUROCHEMISTRY 2. NOCICEPTION AND PAIN Nociception and pain arising from within the pelvis and pelvic floor also involve diverse neuronal mechanisms, although there are some general characteristics. In general, sensations from the pelvic viscera are conveyed within the sacral afferent parasympathetic system, with a far lesser afferent supply from thoracolumbar sympathetic origins An elaborate neurochemical coordination of all components of the central and peripheral nervous systems is necessary for the performance of autonomic and somatic events in the pelvis. As indicated previously, the inferior hypogastric plexus represents the major neuronal center in the pelvis providing a relay station for interconnecting nerve pathways, 930 [395]. Receptive fields in the perineum are understood to be carried out primarily by sensory-motor discharges associated with pudendal nerve afferents [395,389]. While the interactions of sensory afferents are quite complex, likely possibilities by which these pathways exert effects on autonomic efferent function include mediatory effects on spinal cord reflexes and modulatory effects on efferent release in peripheral autonomic ganglia and in peripheral organs. and towards the periphery (opposite to normal - antidromic direction). When the antidromic impulses arrive in the periphery in the area innervated by the activated primary afferent nociceptors, neurogenic inflammation is produced, characterized by reddening (vasodilatation), edema (plasmaextravasation) and hyperalgesia. This neurogenic inflammation is produced by diffusible substances or substances released from the terminals of primary afferent neurons (neuropeptides and probably other autoacoids). The primary afferents involved are thought to be mainly C-fibers, although A-delta fibers also play a role. Although the efferent action of primary afferent fibers is often attributed to axon reflexes, recent studies have indicated that also dorsal root reflexes play a major role in neurogenic inflammation [397]. Neurogenic inflammation has been described in numerous tissues including skin, the joints, the eye, the middle ear, the respiratory, reproductive and digestive system, the dura mater, and most importantly in the context of interstitial cystitis in the genitourinary system [398-400]. Under normal conditions neurogenic inflammation seems to be an adaptive response, promoting rapid increases in tissue substrates, activating cells for local defense and enhancing fluid transport to isolate and dilute invading bacteria and toxins. However, in other settings, due to reasons that are not clear and are the subject of intense research, neurogenic inflammation can become maladaptive. There is increasing evidence for the role of neurogenic inflammation in the pathophysiology of several diseases including asthma, arthritis, migraine and more recently the involvement of neurogenic inflammation has also been suggested in the development of interstitial cystitis [401-403]. In visceral pain conditions neurogenic inflammation does not only play a role in pain and inflammation at the site of the viscus, but also appears to be an important mechanism in referred pain [404]. For example, pain of acute myocardial infarction may sometimes induce a left scapulohumeral periarthritis, an inflammatory condition in the referred zone [405]. It could be hypothesized that neurogenic inflammatory mechanisms in the referred zone might play a role in patients who present with interstitial cystitis and vulvodynia, or pelvic pain and vulvodynia where an inflammatory painful condition develops in the referred zone (the urogenital floor) of the urinary bladder or the pelvis. Evidence for neurogenic inflammation in the somatic referred zone triggered by inflammation of a viscus has been demonstrated in an animal model of uterine pain in the rat, supporting the above hypothesis [400]. Afferent nerve distributions within the vascular and nonvascular smooth muscle of the vagina contain the neuropeptides, galanin and substance P, [82, 390] while extensions into the epithelium and between epithelial cells primarily contain substance P and CGRP [82]. R. CHRONIC PAIN PHYSIOLOGY AND SEXUAL PAIN DISORDERS I. NEUROGENIC INFLAMMATION It is of interest, that there are several urogenital and pelvic pain syndromes, where the chronic pain syndrome seems to be related to an inflammatory etiology : loin pain/hematuria syndrome, interstitial cystitis, irritable bowel syndrome, prostatodynia (prostatitis), VVS. However, despite numerous research efforts, no causes for these inflammatory changes have been identified so far. It is possible that neurogenic inflammation plays a role. It is generally accepted that noxious stimuli can increase the level of pain-producing substances by damage to local tissue. It is important to realize, that substances contributing to nociception are actually present in the terminals of primary afferent nociceptors and that these substances can be released by those terminals when the nociceptor is stimulated. The observation that sensory fibers mediate not only afferent function but also efferent function through the release of modulatory factors dates back to Bayliss (1901), who showed that antidromic conduction in afferent fibers caused vasodilatation [396]. When sensory fibers are stimulated electrically near the spinal cord, electrical impulses will travel from the site of stimulation in both directions: towards the spinal cord (the normal - orthodromic - direction for sensory axons) 931 3% to 43% and varies with culture (the lower estimates are from Northern European countries whereas the higher ones are from the U.S), but also with the setting (3 to 18% in the general population, 3 to 46% in the general practice, 0 to 30% in sexuality clinic settings and 10 to 20% in gynecological clinics) and the gynecologist's initiative to bring up the matter. Several authors found a major difference in the incidence of sexual complaints between selfreported data by the patients and data obtained during a discussion about sexuality initiated by the gynecologist [411-413]. Therefore, in order to detect sexual problems and sexual dysfunctions, explicit questions will have to be asked. II. NEUROPATHIC PAIN : CENTRAL AND PERIPHERAL MECHANISMS There is experimental evidence from several psychophysical studies, suggesting that neuropathic pain mechanisms might be involved in VVS [406-408]. There is general consensus today that both peripheral and central nervous system mechanisms play a role in neuropathic pain [409]. Briefly, neuropathic pain is typically characterized by spontaneous paraesthesias, dysesthesias and by evoked pain (for example pain evoked by mechanical stimuli, such as the pain evoked by tampon insertion or sexual intercourse in patients with VVS). Under normal conditions pain is experienced when impulses reach the brain via A-delta-fiber or C-fiber nociceptive afferents. Minor tissue injuries can cause a reduction in the threshold of nociceptors, resulting in “peripheral sensitization”. This change in threshold is caused by the release of chemical inflammatory mediators into the tissue. Sensitized nociceptors respond to weak, non-noxious stimuli - a clinical phenomenon called “allodynia”. Further, noxious stimuli result in an exaggerated pain response - “primary hyperalgesia”, thus the pain sensation no longer matches the painful stimulus. The clinical phenomena of allodynia and hyperalgesia can also be due to abnormal signal amplification in the CNS, a process called “central sensitization”. In the presence of “central sensitization” signals entering the CNS via nonnociceptive A-beta touch afferents may evoke pain. The cause of increased descending excitatory signals and/or decreased inhibitory signals to allow this central sensitization of dorsal horn cells is unclear. Never the less, the typical initiation and exacerbations of VVS after times of severe stress fits this model of central sensitization. Various medical regimens (tricyclic anti-depressants, venlafaxine, anticonvulsants - usually carbamazepine or gabapentin) have aimed therapy at nerve hyperesthesia. Some offer some pain relief, although total pain resolution with these drugs appears infrequent [410]. Prevalence rates for vaginismus are scant, without the benefit of multiple studies on specific populations. Prevalence estimates for vaginismus range from 1 to 6% (see Table Fugl-Meyer). II. PHYSICAL CONDITIONS ASSOCIATED WITH PAIN ON ATTEMPTED OR COMPLETED VAGINAL ENTRY The following table summarizes various conditions that may be associated with varying degrees of chronic dyspareunia (Table 27). III. GENERAL SEXUAL HISTORY FOR SEXUAL, PAIN DISORDERS Gynecological complaints, diagnostic procedures and/or treatment may have consequences on the sexual functioning of the patient and on her experience of sexuality (and that of her partner). It therefore seems advisable for physicians addressing gynecological concerns to ask each (new) patient about the existence of sexual problems and possible negative sexual experiences prior to procedures and treatments. It is very important that the physician makes it clear to the patient in the way he/she formulates his/her questions that he/she is not making any a priori assumptions about the existence of a sexual relationship, not expressing a heterosexual preference, or making judgments about various aspects of sexuality, sexual behaviour or sexual experience. Sexual problems are imbedded in a somatic, psychological, relational and social context which must be assessed in order to make adequate decisions regarding diagnosis, treatment or referral. S. CLINICAL PRESENTATION OF SEXUAL PAIN DISORDERS I. PREVALENCE Prevalence estimates for dyspareunia range from 932 Table 27 Physical conditions associated with chronic dyspareunia 933 The examination technique to search for the cause of dyspareunia is more detailed and requires much more finesse than a routine pelvic examination. When conducted correctly, it can be highly therapeutic. This is especially true when the sexual partner is also present. Often referred to as an “educational gynecological sexological examination”, the patient watches in the mirror as the doctor gathers information and tells the patient about her genital anatomy, clarifying normal (or abnormal) structures. This can correct misinformation and resultant negative selfimage, and can clarify how any physical changes relate to sexual problems. If not precluded by her pain, additional transvaginal sonographic assessment for deep dyspareunia, increases both the sensitivity and specificity of the exam, especially any ovarian abnormality [415]. IV. EDUCATIONAL GYNECOLOGICAL SEXOLOGICAL EXAMINATION In order to detect or exclude physical illness or abnormalities that cause pain on (attempted) vaginal entry (Table 28), the non-physician and physician will have to work together. Especially in the case of dyspareunia or vaginismus, it is not always desirable or practical to perform a medical examination straight away. The patient and care provider together must make decisions about timing, who is present, and the extent of the examination. Table 28. [414] 1. PAIN Where does it hurt? How would you describe the pain? It is extremely important that the patient knows in advance that she has total control over the situation, knows exactly what is going to happen and that she is the one who decides who is going to be there and who is not, and that she knows that during the examination, her personal boundaries will be respected and safe-guarded [416]. Through this examination, the foundations are laid for a meaningful discussion afterwards, in which all the findings are explained and at which time, further sexual complaints may come to light. Is the pain with penile contact to the opening of your vagina, once the penis is partially in, with full entry, after some thrusting, after deep thrusting, with your partner’s ejaculation, after withdrawal, with subsequent micturition? Do you find your body is tensing when you or your partner attempts to insert his penis? What are your thoughts and feelings at this time? How long does the pain last? Does touching elsewhere in the genital area cause pain? Does it hurt when you ride your bicycle or when you wear tight clothes? Do other forms of penetration hurt (tampons, fingers)? 2. PELVIC FLOOR MUSCLE TENSION Although based on level 5 evidence, this is recommended to lessen the common occurrence of women having to seek multiple health care providers before an accurate diagnosis is made. Do you recognise the feeling of pelvic floor muscle tension during sexual contact? Do you recognise the feeling of pelvic floor muscle tension in other (non-sexual) situations? 3. AROUSAL 1. THE CONTEXT Do you feel subjectively excited when you attempt intercourse? Does your vagina become sufficiently moist? Do you recognise the feeling of drying-up? When a component of vaginismus is indicated by the history, the patient is told ahead of time that the use of speculum or other means of internally examining the pelvis will not be part of this examination. It is recommended to ask the woman if there is anything she can think of that will facilitate the exam and to impart to her a sense of control on what is happening. The physician is seated comfortably on a low stool and the examination couch adjusted for the woman to be sitting so she may see in a hand mirror, but her wish not to will be respected. Verbally checking how the woman is coping with the exam from time to time is recommended. Non-verbal communication the patient's behaviour and that of her partner during the examination are noted, and the physician, too, must be aware of his or her non-verbal signals. 4. CONSEQUENCES OF THE COMPLAINT What do you do when you experience pain during sexual contact? (Continue/stop intercourse/continue to make love without intercourse?) Do you currently continue to include intercourse or attempts at intercourse, or do you use other ways to make love instead? If so, are you both clear intercourse will not be attempted? What consequences does the pain have on the rest of your relationship? 5. BIOMEDICAL ANTECEDENTS When and how did the pain start? What tests have been done? What treatment have you received 934 2. ADEQUATE SPREADING Permission is asked to gently spread the vulva or the patient is asked to spread the vulva herself with her fingers. This enables her to observe the consequences of pelvic floor muscle activity. By bearing down or coughing, she is able to see the introitus becoming larger. The vulva is carefully inspected, including the labia minora, majora and the crease between, the clitoral hood and clitoris, the posterior fourchette, vestibule, hymen and hymenal edge. For women with introital dyspareunia, sites of allodynia are investigated using a cotton bud (Q-tip) applying the stimulus of touch along the outer edge of the hymen which is also the inner edge of the inner surfaces of the labia minora. The skin at the opening of Skene's ducts must also be tested for allodynia as it is commonly involved in vulvus vestibulitis. Figure 7: The vulvalgesiometer 3. INTERNAL EXAM It may be possible to proceed to the internal exam on this first visit when the characteristic features of vaginismus were not present in the history and are not present during this exam. With the woman bearing down, the insertion of physician's finger or if necessary, something smaller such as Q-tip, with her permission, confirms vaginal entry without any pain. (Even with VVS, if the woman is opening the introitus and the finger is carefully placed without pressure on the edge, especially the posterior fourchette, the procedure is painless). 5. THE PELVIC FLOOR Involuntary contraction on the gynecology couch does not infer that this is also necessarily present at home. Conversely, some women can undergo a gynecological examination without any problem, but have vaginistic reactions in other circumstances, depending on what they find threatening. In many cases, the pelvic floor muscles are chronically contracted and feel like “steel cables”. Physician assessment of pelvic floor muscle tone is imprecise but still of some value. The physician places his or her finger between the woman's labia just in front of the vaginal opening and applies very gentle pressure. The woman is asked to bear down whilst the physician slowly moves the finger inside, keeping it dorsally curved to feel the pelvic floor muscle without touching painful areas at the vestibular margin. At the end of the examination the finger is slowly withdrawn again as the patient bears down. The use of a lubricant will facilitate the examination and also prevent tissue damage. 4. MEASUREMENT OF ALLODYNIA IN VVS The cotton-swab test is widely used [382, 417]. As the Q-tip is repeatedly placed on the edge of the vestibule in a clockwise fashion, the woman's verbal and physical reactions are noted and she may be asked to grade the pain (e.g. out of 1-4). However, the cotton swab test is prone to measurement error when used for experimental purposes or to measure treatment outcome [407]. Therefore a new simple mechanical devise, the vulvalgesiometer (Figure 7) has been developed [418]. The vulvalgesiometer is cost- and time-effective and easy to use. It can be used as a diagnostic tool capable of differentiating among women with different types of genital pain, and because of its large range of exertable pressures, it may aid in quantifying the severity of pain (mild, moderate, severe) experienced by these women. This device also has applications in quantifying changes in vestibular sensitivity as a result of treatment. V. QUESTIONNAIRE ASSESSMENT OF PATIENTS WITH DYSPAREUNIA It is worthwhile to administer a questionnaire before and after treatment - see Chapter 5. With the aid of such a measurement instrument, possible comorbidity can be detected and the effect of the intervention can be evaluated. Questionnaires in the English lan- 935 Evidence for psychological factors involved in the causation or maintenance of the sexual pain disorders is grouped into the following categories : guage have the advantage that they are well-known in the international literature, which facilitates comparisons of international publications, and that they have been used often in research, which facilitates comparisons between results and populations. However, for local use these questionnaires have to be translated and validated again. This is recommended because of cultural differences. I. Psychometric data, showing differential presence of psychopathology in patients and non-patient comparison groups (Table 28) [5, 101, 419-421] ; II. Psychometric data, showing differences on measures of personality traits between patients and non-patient comparison groups (Table 29) [78, 95, 340, 407, 420-432] ; A simple and effective instrument to obtain measurement data is the Visual Analogue Scale. From time to time during the treatment, the woman marks a score on a sliding scale to represent the amount of progress that has been made. III. Experimental data on psychological processes (Table 30) [78, 407, 424, 433-437] ; IV. Psychometric data successfully predicting treatment outcome (Table 31) [438-442]. T. PSYCHOLOGICAL ASPECTS OF SEXUAL PAIN DISORDERS A summary of findings from this database follows : (** : If more than one study with results pointing in the same direction are retrieved ; * : if only single study results were retrieved ; see Table 32 for summary of these findings.) Note, psychopathology and impaired psychological functioning may be caused as well as effect of the various forms of sexual pain. I. OVERVIEW AND DATABASE The following psychological factors in the causation and/or maintenance of sexual pain disorders will be discussed : II. VULVAR VESTIBULITIS a. individual psychological characteristics of the women, resulting in increased vulnerability for sexual pain : personality traits, personality disorders, psychiatric comorbidity Vulvar vestibulitis is thought to underlie the vast majority of superficial (introital) dyspareunia. b. characteristics of the woman's sexual relationship 1. INDIVIDUAL PSYCHOLOGICAL AND c. psychological processes PERSONALITY CHARACTERISTICS Higher rates of psychopathology in women with VVS were found with regard to depression** and anxiety disorders* (see Tables 28 & 32). d. psychological variables enabling prediction of treatment outcome. As to the establishment of causative vs. correlational relationships between psychological factors and the origin and maintenance of sexual pain, empirical evidence of the highest level available is needed. Confidence in the hypothesized relationships is highest, and causal inferences can more safely be made, when based on the results of (replications of) prospective, randomized, and controlled trials, in which the factors under scrutiny are kept under strict experimental control. No causal inferences can be made from correlational, cross-sectional, and retrospective studies, or from treatment studies, although these types of evidence provide circumstantial support and may suggest directions for future controlled research. On self-report measures (see Tables 29 & 32), scores on neuroticism of women with VVS are found to be in the normal range**. As to self-reported symptoms of depression, state anxiety, phobic anxiety, social anxiety, and obsessive-compulsive behavior, results are conflicting, finding both higher** and equal** scores, compared with normative groups. Trait anxiety scores are consistently found to be elevated**. The personality trait of shyness was found higher*. Results with regard to hostility scores and paranoid ideation in women with VVS are left unresolved, with studies both finding higher* and equal** scores. The personality trait of psychoticism has 936 Table 29. Psychopathology in women with sexual pain disorders Refs: 5, 101, 419-423 937 Table 30. Psychological characteristics of women with sexual pain disorders Refs 78, 95, 340, 407, 420-434, 442 938 Table 30. Psychological characteristics of women with sexual pain disorders Refs 78, 95, 340, 407, 420-434, 442 939 Table 30. Psychological characteristics of women with sexual pain disorders Refs 78, 95, 340, 407, 420-434, 442 940 Table 30. Psychological characteristics of women with sexual pain disorders Refs 78, 95, 340, 407, 420-434, 442 941 Table 30. Psychological characteristics of women with sexual pain disorders Refs 78, 95, 340, 407, 420-434, 442 942 BDI (Beck Depression Inventory): Beck AT, Steer RA (1987) Manual for Beck Depression Inventory. Harcourt Brace Jovanovich, New York. BSI (Brief Symptom Inventory): Derogatis LR, Melisaratos N (1983) The Brief Symptom Inventory: an introductory report. Psychol Med 13: 595-605. Campion Questionnaire: Campion MJ (1988) Psychosexual trauma of an abnormal smear. Br J Obstet Gynaecol 95: 175-181. CCEI (Crown-Crisp Experiential Index): Crown S, Crisp AH (1979) Crown-Crisp Experiential Index. Hodder & Stoughton, London. DAS (Dyadic Adjustment Scale): Spanier GB (1976) Measuring dyadic adjustment: new scales for assessing the quality of marriage and similar dyads. J Marriage Fam 38: 15-28. EPQ (Eysenck Personality Questionnaire): Eysenck HJ, Eysenck SBG (1975) Eysenck Personality Questionnaire (Adult). Hodder & Stoughton, Tonbridge. GAS (Groningen Arousability Scale): Weijmar Schultz WC, van de Wiel HBM (1991) Sexual functioning after gynecological cancer treatment. Unpublished Master’s Thesis, State University Groningen, the Netherlands. SCL-90: Arrindell WA, Ettema H (1986) SCL-90: Handleiding bij een multidimensionele psychopathologie indicator. Swets & Zeitlinger, Lisse NL SCL-90-R: Derogatis LR (1977) SCL-90-R: Administration, Scoring and Procedures Manual I. Clinical Psychometrics Research, Baltimore. SEI (Coopersmith Self-Esteem Inventory): Coopersmith S (1981) Coopersmith Self-Esteem Inventory. Consulting Psychologists Press, Palo Alto, CA. SHF (Sexual History Form): Nowinsky JK, LoPiccolo J (1979) Assessing sexual behaviours in couples. Sex Mar Ther 5: 225-243. SPQ (Social Problems Questionnaire): Corney RH (1988) Development and use of a short self-rating instrument to screen for psychosocial disorder. J Royal Coll Gen Pract 38: 263-266. SSS (Sexual Self-Schema): Andersen BL, Cyranowski JM (1994) Women’s sexual self-schema. J Pers Soc Psychol 63: 891-906. L-W MAS (Locke-Wallace Marital Adjustment Scale): Locke HJ, Wallace KM (1959) Short marital-adjustment and prediction tests: Their reliability and validity. Marriage Fam Liv 3: 251-255. MMPI-SV (Minnesota Multiphasic Personality Inventory, Short Version in Dutch): Luteijn F, Kok AR (1985) Nederlandse Verkorte MMPI. Swets & Zeitlinger, Lisse NL. MPS (Multidimensional Perfectionism Scale): Frost RO, Marten P, Lahart C et al. (1990) The dimensions of perfectionism. Cognitive Ther Res 14: 449-468. PCS (Pain Catastrophizing Scale): Sullivan MJL, Bishop SR, Pivik J (1995) The Pain Catastrophizing Scale: development and validation. Psychol Assess 7: 524-532. QSD (Questionnaire for Screening Sexual Dysfunctions): Vroege JA (1993) Vragenlijst voor het signaleren van seksuele dysfuncties. AZU/NISSO, Utrecht NL. SOS (Sexual Opinion Survey): Fisher WA, Byrne D, White LA, Kelley K (1988) Erotophobia-erotophilia aas a dimension of personality. J Sex Res 25: 123-151. STAI (Spielberger State-Trait Anxiety Inventory): Spielberger CD (1972) Current trends in theory and research on anxiety. Academic Press, New York, pp. 3-19. TCI (Temperament and Character Inventory): Cloninger CR, Przybeck T, Svrakic D, Wetzel R (1994). The Temperament and Character Inventory (TCI): A guide to its development and use. Washington University Press, St. Louis, Missouri. Table 31. Psychological processes in sexual pain disorders in women: Results of experimental investigations Refs 78, 407, 424, 428, 433-437 943 Table 31. Psychological processes in sexual pain disorders in women: Results of experimental investigations Refs 78, 407, 424, 428, 433-437 944 Dysfunction type: DYS = dyspareunia; VVS = vulvar vestibulitis syndrome; VAG = vaginismus. BSI = Brief Symptom Inventory; L-W MAS = Locke-Wallace Marital Adjustment Scale; MPQ = McGill-Melzack Pain Questionnaire; SAI = Sexual Arousability Inventory; SOS = Sexual Opinion Survey. sures of sexual functioning were reported, which results were found to be maintained over time. been found to be both higher* and equal** as has the personality trait of somatization. As to the extraversion trait, women with VVS did not have higher scores than normative groups**. Women with VVS, however, did appear to be more perfectionistic*, and harm avoiding*, particularly fearing of negative evaluation by others*. 2. SEXUAL VVS Prediction of treatment by means of psychological or psychosocial variables (see Table 30) has been investigated in VVS in three studies. Psychosocial variables predictive for better outcome were: higher socioeconomic status*, lower education*, and childlessness*. Psychological factors at pain onset and psychological test scores (marital adjustment, neuroticism, psychopathology) were not predictive*. Willingness to be psychologically evaluated was highly predictive for positive outcome of limited vestibulectomy*, as was cooperation of patient in postoperative counseling*. High scores on instruments measuring fear of negative evaluation by others, phobia re vaginal entry and the Personality Assessment Screener have been associated with poor outcome. No replications of prediction models have been reported. RELATIONSHIPS OF WOMEN WITH With regard to personality traits assumed to be directly related to the domain of sexuality, they are found to score higher on erotophobia*, and to have more self-reported difficulties with sexual arousal and vaginal lubrication during partner interaction** as compared to functioning during masturbation*. They were also found to lack sexual pleasure more often*, and to have more negative feelings about sexual interaction*. Their marital satisfaction was equal to normative groups** as was the strength of positive sexual self-schema*. 5. CONCLUSIONS RE WOMEN WITH 3. PSYCHOLOGICAL PROCESSES DYSPAREUNIA FROM VESTIBULITIS As to psychological processes causing or maintaining dyspareunia (see Tables 29 and 31), the level of pain ratings in VVS patients is predicted by their level of marital adjustment*, where lower marital adjustment is associated with higher pain ratings. Heat pain thresholds, and unpleasantness thresholds, in women with VVS are lower in comparison with asymptomatic women*, while perceived pain during suprathresholds heat stimulation is higher in women with VVS*. The thresholds for tactile (pressure) sensitivity at several vestibular sites, labia minora, and deltoid muscles are lower in women with VVS*, compared with asymptomatic women. This lowered sensitivity is stable over time. Pressure pain thresholds at vestibular sites, labia minora, deltoid and volar forearm are lower in women with VVS*. Women with VVS report higher distress for sustained suprathreshold pressure, and tolerate less pressure than controls*. Attentional bias for painrelated stimuli is demonstrated in women with VVS*, as compared with normal controls, leading to hypervigilence for pain-related stimuli*. The level of hypervigilence is largely accounted for by state and trait anxiety levels. In sum, in women with vulvar vestibulitis, elevated comorbid psychopathology was found (depression and anxiety disorders). The self-report findings on psychological characteristics, however, were not unequivocally found to support psychopathology findings. Both more problematic psychological functioning and unaffected functioning have been reported, possibly reflecting differences in study samples and instrumentation or true heterogeneity of women with VVS. Increased trait anxiety in women with VVS, however, has been found in two studies, and may represent a stable characteristic. Single study findings of women with VVS included elevated rates of shyness, perfectionism, the temperament trait of harm avoidance, increased tendency to have catastrophizing thoughts and negative feelings towards sexual interaction, erotophobia, and problems with subjective sexual arousal and lubrication during sexual interaction with partner, but not during masturbation. Psychopathology and impaired psychological functioning may be cause as well as effect of vulvar vestibulitis. Women with VVS have been found to be more sensitive to thermal and tactile stimulation, reflected in lowered thresholds for sensitivity and the experience of pain on stimulation. An etiological element may be the attentional bias of hypervigilence for pain-relation stimuli. These latter experimental findings have not yet been replicated. 4. PSYCHOLOGICAL VARIABLES AND OUTCOME The psychological treatment of vulvar vestibulitis has been evaluated in three controlled trials [429, 444, 445]. Significant improvement in experienced pain, and in intercourse frequency and other mea- 945 Table 32. Psychological and psychosocial predictors of treatment outcome of women with sexual pain disorders Refs: 438-442 946 se in women with dyspareunia was found to be impaired when confronted with audiovisual representation of coitus*, as opposed to viewing audiovisual stimuli representing other forms of sexual interaction (oral heterosexual stimulation), while subjective sexual arousal did not differ between women with dyspareunia and controls*. III. DYSPAREUNIA NOT IDENTIFIED AS VVS 1. INDIVIDUAL PSYCHOLOGICAL AND PERSONALITY CHARACTERISTICS Higher rates of psychopathology in women with dyspareunia not stated to be due to VVS were found with regard to depression** and anxiety disorders*, more specifically : generalized anxiety disorder*, simple phobia*, obsessive-compulsive disorder*, and social phobia*. Equal rates of psychopathology in women with dyspareunia, compared with healthy controls, were found with regard to posttraumatic stress disorder*, and eating disorder* (see Tables 28 and 32). Psychological treatment of dyspareunia (non VVS) has thus far not been evaluated in controlled comparisons nor has prediction of treatment outcome by means of psychological or psychosocial variables. 4. CONCLUSIONS RE WOMEN WITH DYSPAREUNIA NOT FURTHER CLARIFIED Summarizing, women with dyspareunia are found to have elevated rates of clinically relevant comorbid depression and anxiety disorders. Sexual traumatization appears not to play a significant role in etiology. Self-report measurement of psychological characteristics corroborates the presence of depressive and anxious symptoms, both on the experiential and the behavioral level. Experiential and behavioral signs of hostility and psychotic symptoms also appear to be more frequently present. As to sexual functioning, women with dyspareunia are found to be more erotophobic, reflecting negative and conservative attitudes towards sex, and aversion to engage in sex. They have more problems with experiencing sexual arousal. Relationship discord is found to be increased in women with dyspareunia. Impairment of genital responding was found to be produced by specific sexual stimulation (audiovisual representation of penile-vaginal intercourse) during laboratory investigation. This effect has thus far not been replicated. In women with dyspareunia equal frequency of childhood sexual trauma has been found*, when compared with the general female population. On self-report measures (see Tables 29 and 32), women with dyspareunia are found to have higher scores on neuroticism*, depression** and state anxiety**. Phobic anxiety in women with dyspareunia is found higher**, as are obsessive-compulsive behaviors**, and social phobia (interpersonal sensitivity)**. Women with dyspareunia also report more symptoms of hostility**, more (psycho)somatic complaints (somatization)*, higher paranoid ideation*, and more psychotic symptoms*. 2. SEXUAL RELATIONSHIPS OF WOMEN WITH DYSPAREUNIA With regard to personality traits assumed to be directly related to the domain of sexuality, they are found to score higher on erotophobia*, and to have more negative feelings about sexual interaction*. IV. VAGINISMUS With regard to sexual functioning, they appear to have more problems with sexual arousal**. 1. INDIVIDUAL PSYCHOLOGICAL AND PERSONALITY CHARACTERISTICS They are shown to be suffering from increased relationship discord**. Higher rates of psychopathology in women with vaginismus were found with regard to agoraphobia without panic disorder*, and obsessive-compulsive disorder* (see Tables 28 and 32). 3. PSYCHOLOGICAL PROCESSES As to psychological processes causing or maintaining dyspareunia (see Tables 30 and 32), the level of pain ratings in dyspareunia patients is predicted by their level of depression*, where higher depression scores are associated with higher pain ratings. Compared with nonsymptomatic women, genital respon- In women with vaginismus, when compared with the general female population, equal frequency* of childhood sexual trauma was found in one study, whereas another study found elevated frequency*. 947 Table 33. Overview of psychological aspects of sexual pain disorders 948 On self-report measures (see Tables 29 and 32), conflicting findings were reported. Women with vaginismus are found to have equal and higher scores on neuroticism**, depression**, state anxiety**, phobic anxiety**, social phobia**, obsessivecompulsive behaviour**, paranoid ideation**, psychoticism**, somatization**, and hostility**. strong wish to become pregnant*, better sexual knowledge*, good compliance with homework assignment by third treatment session*, and lower pretreatment ratings of the female partner of marital tension*. Negatively associated with treatment length were: pretreatment sexual desire problems*, fear of sexually transmitted diseases*, negative parental attitudes towards sex*, having undergone previous operations for vaginismus*, and history of organic abnormality (septum, vaginitis)*. With respect to dispositional traits, women with vaginismus were equal to the normal population on extraversion**, and negative sexual self-schema*. They showed elevated traits of low self-esteem*, less positive sexual self-schema*, and hysterical personality*. 2. SEXUAL No predictive value was found of: history of sexual abuse*, presence of additional sexual dysfunction in either partner*. No replications of prediction models have been reported. RELATIONSHIPS OF WOMEN WITH VAGINISMUS Rates of marital discord were equal to the general population*. 5. CONCLUSIONS RE WOMEN WITH With regard to their sexual functioning, women with vaginismus reported less self-stimulation*, more problems with sexual desire* and arousal*. Summarizing, women with vaginismus were found to have significantly increased comorbid anxiety disorder, while depression rates were not found to be increased. The role of childhood sexual trauma is unclear, since different frequency rates were found, and the presence of increased rates of posttraumatic stress disorder has not been investigated as yet. Psychological characteristics, measured with self-report instruments do not unequivocally corroborate the presence of anxiety disorders. Personality traits found to be more often present in this group suggest the presence of self-focused attention and negative self-evaluation in the etiology or maintenance of vaginismus. Sexual functioning may be impaired with regard to sexual desire and arousal response during sexual activity. Experimental evidence thus far documented the role of experienced threat in increased pelvic floor muscle tension, but did not discriminate between women with and without vaginismus. The causation and maintenance of vaginismus by psychological factors thus remain unresolved although fear of penetration and associated attentional bias may play a role. VAGINISMUS 3. PSYCHOLOGICAL PROCESSES As to psychological processes causing or maintaining vaginismus (see Tables 30 and 32), women with and without vaginismus are found not to differ in baseline pelvic floor muscle tension*, or in the ability to control pelvic floor muscles while performing exercises (short flick contractions and 10-sec holding contractions)*. Women with vaginismus and asymptomatic women do not differ in their EMGmeasured pelvic floor muscle response to threatening and sexual-threatening stimuli*. Erotic stimulation does not increase pelvic floor muscle activity in women with vaginismus. Experienced threat of the stimuli correlates significantly with EMG-measured muscle activity*. Thus far, no randomized controlled trials of psychological treatment for vaginismus have been published. 4. PREDICTION OF TREATMENT U. PELVIC FLOOR AND SEXUAL PAIN DISORDERS Prediction of treatment by means of psychological, psychosexual and psychosocial variables has been investigated in vaginismus in three non-controlled studies (see Table 30). Problems with the pelvic floor musculature have been closely linked with the diagnosis and treatment of the “sexual pain disorders”. For example, both the AFUD and DSM nosologies have used the concept Psychological variables predictive for better outcome were : attribution of problem to psychological causes*, positive attitude towards own genitalia*, 949 of vaginal muscle spasm to classify vaginismus [56, 142]. The traditional treatment for vaginismus, «vaginal dilatation», was presumed by many to follow from this definition. Poor pelvic muscle strength, and increased tonicity have been suggested as important correlates of dyspareunia resulting from VVS. This idea has resulted in the development of pelvic floor biofeedback and physical therapy as treatment modalities [446, 447]. reliably ? 2) can vaginal spasm be assessed reliably ? 3) are there differences in baseline tonicity or voluntary control over the pelvic musculature that distinguish women suffering from vaginismus from controls ? 4) are therapies based on self-placement of progressively larger vaginal inserts effective ? 2. DIAGNOSIS OF “VAGINISMUS” Perhaps because there has been so little controversy concerning the diagnosis, there have been very few studies examining the reliability and/or validity of diagnosis. In two consecutive clinical case studies (level 4b), the authors have pointed out that it is often hard to distinguish vaginismus from dyspareunia resulting from VVS [342, 451]. A Dutch group has shown in one retrospective and one prospective study based on structured gynecological examinations, interviews and psychometric testing, level 2b, that it is very difficult to distinguish vaginismus from dyspareunia [340, 341]. Finally, in a formal diagnostic reliability study, level 2b, it was shown that although gynecologists and pelvic floor physical therapists can distinguish women suffering from sexual pain disorders from matched controls, they could not reliably distinguish women diagnosed with vaginismus from those diagnosed with VVS based on vaginal spasm, pelvic hypertonicity or pain. Furthermore inter-gynecologist reliability for the diagnosis of vaginismus was quite poor [452]. Overall, part of this difficulty in differentiating vaginismus from dyspareunia has been the idea held by some diagnosticians, who have understood the concept of “interference with intercourse” to mean “the total preclusion of intercourse”. Therefore, a “not stoic” woman with dyspareunia from what ever cause who does not want to tolerate the pain of penetration would be diagnosed with “vaginismus”. For this reason, the diagnosis of vaginismus should only be made if structural or other physical abnormalities have been ruled out or addressed [64]. Additionally, a woman without evidence of VVS or other variety of dyspareunia, displays signs of fear of vaginal entry with tightening of pelvic and abdominal muscles (and often thigh, jaw, hand muscles, etc), may nevertheless experience full penetration by a persistent partner who does not desist despite lack of erotic quality of the interaction. She has “vaginismus” but can just about tolerate full entry +/- some thrusting. Clinicians and researchers working with “sexual pain” patients are often faced with a bewildering array of terms to describe and define muscle states that are presumed to be linked to clinical pain problems. Among the terms used are the following : tonicity, contracture, spasm, compliance, stiffness, tetany, dsytonia, trigger point etc. Although there are formal definitions for many of these terms [448], these definitions are rarely used consistently in the clinical or research literatures. With respect to the sexual pain disorders of vaginismus and dyspareunia, this has resulted in much confusion. The basic issue to be addressed here is the following: can sexual pain be considered a disorder of the pelvic floor ? 1. THE ENTITY OF “VAGINISMUS” It is remarkable that there has been almost no controversy until very recently, concerning the spasm based definition of vaginismus. This definition can be traced back to the writings of Trotula of Salerno who described the condition as a result “…of tightening of the vulva so that even a woman who has been seduced may appear a virgin” [449]. This idea of vulval tightening was transformed into vaginal spasm by the 19th century so that Sims (1861) described the condition as “spasmodic contraction of the sphincter vaginae...”. Despite the absence of research confirming this spasm criterion, the 1998 consensus diagnostic formulation is as follows : “recurrent or persistent spasm of the musculature of the outer third of the vagina which interferes with vaginal penetration and causes personal distress” [142]. This consensus definition did not essentially change the current ICD 10 or DSM diagnostic statements except for changing the “interference criterion” from interference with intercourse or penile entry specifically to interference “with vaginal penetration in general”. Further revision of the definition omitting reference to spasm and noting the variable avoidance typical of this syndrome, has just been published [64] see p77. 3. VAGINAL “SPASM” IN VAGINISMUS Issues relating to the role of the pelvic floor in vaginismus can perhaps be usefully divided into four separate questions : 1) can vaginismus be diagnosed Because all previous definitions of vaginismus were based on the concept of vaginal spasm and because 950 the differential diagnosis of vaginismus from dyspareunia is questionable, there is reason to suspect that the diagnosis of vaginal muscle spasm may also not be reliable. In fact, the general validity of the concept of muscle spasm has been called into question [453]. As far as we are aware, only one study has directly investigated whether muscle spasm specifically characterizes vaginismus [452]. The results of this study strongly suggest that vaginal muscle spasm does not characterize vaginismus and that different professionals diagnose spasm very differently. Interestingly, less than a quarter of the women in the vaginismus group attributed their difficulties with intercourse to vaginal spasm. tion” but a gradual reduction of reflex protective involuntary tightening. Although this intervention is generally acknowledged to be highly effective and necessary for treating vaginismus [454], there has never been a randomized controlled treatment study examining it or any other therapy protocol. Although there are numerous poorly or semi-controlled therapy outcome studies for vaginismus, the overall quality of the evidence is quite poor (level 3b). These studies will not be reviewed here because there have been several recent comprehensive and critical reviews of this literature [141, 338, 455, 456]. Despite the differing evaluation methodologies used in these reviews, and despite strong clinical support for these approaches, the reviews conclude the insert treatment and psycho-education, desensitization etc. have not been scientifically proven as effective treatments. There is also concern over the appropriate criterion for success in these therapies. While the traditional criterion is vaginal penetration, several recent authors criticized this criterion and suggested that the experience of penetration alone without pleasure is not adequate [457, 458]. It has also been suggested that vaginismic symptoms sometimes serve the function of maintaining a dyadic emotional equilibrium. If this is indeed the case, then outcome criteria must take into account the removal of this coping mechanism and subsequent emotional and physical adjustments [459]. Clinical experience but not as yet scientific study, confirms frequent comorbidity in the partner - the history of sexual hesitancy generally (relatively infrequent self-stimulation and a certain degree of emotional comfort with the sexual infrequency with the partner), or specifically avoidance of sexual intimacy with his partner. 4. MUSCLE TONE OR STRENGTH IN VAGINISMUS Four studies have investigated this issue using a variety of measurement techniques including vaginal and non-vaginal EMG, pelvic floor physical therapist and gynecologist ratings (level 2b) [435, 436, 452, 453]. EMG pelvic floor measurements were taken in response to a) film stimuli displaying erotic, neutral, sexually and non-sexually threatening situations, b) gynecological examinations, and c) instructions to consciously contract and relax vaginal/pelvic muscles. In only one of the studies [452] did EMG measures differentiate vaginismic women from matched controls. Such studies are intrinsic problematic. Women with typical/severe “vaginismus” have never been able to tolerate the insertion of a finger, a tampon, a penis, speculum and before any therapy would not be likely to comply with these protocols. Indeed, in the above study, over half the women suffering from vaginismus refused to insert the EMG sensor for one of the two testing sessions. There was, however, consistent data from this study indicating that a structured protocol of manual measurement of the pelvic floor musculature carried out by physical therapists is reliable and can differentiate women with vaginismus from matched normal controls. II. DYSPAREUNIA 1. THE QUESTION OF MUSCLE TONE Almost all the research regarding the contribution of pelvic floor muscle physiology to dyspareunia is linked to the work of Howard Glazer who has focused primarily on the use of vaginal electromyographic biofeedback (“Glazer protocol”) as a treatment modality for VVS/vulvodynia. The discussion will focus on two questions : 1) are there demonstrable pelvic floor muscular differences in women with dyspareunia ? 2) are pelvic floor focused therapies for dyspareunia effective ? 5. THERAPEUTIC RESULTS Since Masters and Johnson, most therapies for vaginismus have used vaginal “dilatation” as a major treatment intervention: Initially the woman becomes accustomed to self touch to the introitus and insertion of her own finger though the introitus and part way into her vagina. She then places the first of a series of inserts of gradually increasing diameter into her vagina. In reality of course there is no “dila- 951 2. PELVIC FLOOR IN WOMEN WITH III. SUMMARY DYSPAREUNIA In a series of uncontrolled consecutive patient outcome studies using vaginal electromyographic feedback, level 4b, the investigator has reported impressive pain reduction/return to intercourse results for women suffering from VVS and vulvodynia [446, 460-462]. Although psychiatric and psychological texts often attribute sexual pain to the pelvic muscle dysfunction, standard medical texts focusing on the pelvic floor rarely, if ever, mention vaginismus or dyspareunia [464]. Such texts deal with a wide variety of disorders some of which can be described as urogenital pain syndromes e.g. “levator ani syndrome” or “proctalgia fugax”. These syndromes, however, generally refer to perineal or rectal pain rather than vulvovaginal pain. There does appears to be a “minority multidisciplinary movement” among some specialists to consider the pelvic floor as an “integrated functional structure” and to subsume a variety of related “voiding, sexual, genital and defecatory behaviors and problems” under the umbrella of pelvic floor dysfunction. While this idea is an intuitively appealing one, there is currently no empirical support for it. As a result, the author has suggested that changes in resting pelvic muscle tone and contractility may characterize these disorders. Another study, level 2, also examined this issue using a Glazer based vaginal EMG protocol and structured physical therapist palpation [452]. Their EMG data confirm differences in muscle strength but not muscle tone between VVS sufferers and matched controls. However, for physical therapist-based palpation data, the authors found increased pelvic floor tonicity and lowered muscle strength in women with VVS compared with normal matched controls. It is remarkable that there is no empirical evidence to support the 500 year old definition of vaginismus as related to spasm of the muscles of the pelvic floor. The existing evidence directly contradicts it. While there is some indication of differences in resting muscle tone or strength between vaginismus, dyspareunia and no pain controls, these are not well established and could equally well be the result of or the expectation of pain rather than the cause. In fact, there is accumulating basic research to support the idea that the pelvic floor musculature, like other muscle groups is indirectly innervated by the limbic system and therefore highly reactive to emotional stimuli and states [466-468]. Combined with the findings summarized above from vaginismic women, there does appear some indication that pelvic floor muscle tone and strength measures for women suffering from VVS are intermediate between those of women with vaginismus and no pain controls. 3. THERAPEUTIC RESULTS Bergeron et al., level 2b, have carried out a prospective, randomized controlled treatment outcome study which compared the Glazer treatment protocol to cognitive-behavioral group pain management and vestibulectomy [463]. There is encouraging preliminary information to suggest that vaginal EMG biofeedback, pelvic floor physical therapy and cognitive behavioral therapy may be useful interventions for VVS [444]. If this is true, it also seems likely that this would be true for vaginismus. Such “limited therapy outcome evidence” however, cannot be used to characterize the nature of the problem. Overall, “sexual pain” cannot be currently characterized simply as a pelvic floor disorder. The problems of vaginismus and dyspareunia, in fact, may not constitute discrete categories at all but may result from the interaction of a variety of factors including genital pain, emotional and behavioral reactions to vaginal penetration/ touch, sexual interest and arousability, the presence/absence of infection, structural anomalies, disease and pelvic floor dysfunction. Glazer type biofeedback resulted in significant clinical improvement as compared with baseline and approximately a 40% reduction in pain. The same authors have also carried out an uncontrolled retrospective, level 4b, consecutive case investigation of whether pelvic floor physical therapy including but not limited to biofeedback was useful in the treatment of VVS [438]. The pelvic floor physical therapy typically lasted 68 sessions and included a variety of manual techniques, biofeedback, electrical stimulation and homework exercises designed to stretch, strengthen, relax and heighten awareness of the pelvic floor muscles. Approximately 50% of the patients reported complete to great improvement and another 20% reported moderate gains. 952 enough to cause sexual and psychological distress [410]. The syndrome is difficult to treat. Topical treatment of any kind usually increases the amount of pain. Oral therapy using tri-cyclic antidepressants or anticonvulsants offer a reduction, but not a total resolution [410]. V. MUCOUS MEMBRANES AND SEXUAL PAIN DISORDERS I. INTRODUCTION 2. CHRONIC VULVAR DERMATOSES A wide variety of chronic vulvar skin conditions can cause sexual pain both intermittently and continuously. While not common in the general population, lichen simplex chronicus, lichen sclerosis and lichen planus can cause chronic vulvar inflammation and, hence, vulvar pain [469, 473, 474]. The diagnosis of these conditions can be more easily discerned by experienced clinicians. Lichen simplex chronicus results when chronic scratching produces inflammation of the skin and results in an itch-scratch cycle. The cycle can be interrupted by topical steroid and oral antihistamine therapy [475]. Lichen sclerosis is an indolent chronic condition of unknown etiology where thinning of the epidermis occurs, resulting in a parchment-paper appearance of the skin. Underlying subepithelial inflammation can result in mild to intense itching that is possible to reduce better with topical steroid therapy than with topical testosterone [476]. Lichen planus results in superficial ulcers of the epithelium often resulting in intense pain. Patients can have concomitant vaginal mucosal inflammation that results in a profuse irritating vaginal discharge. Often, patients with lichen planus have evidence of inflammation in other mucous membrane areas such as ulcers of the gums, esophagus or bowel in a Behcet-like syndrome. Prolonged topical steroid, topical tacrolimus (an inhibitor of interleukin-1) or other anti-inflammatory therapy is needed of the ulcerated and inflamed areas [477]. Sexual pain disorders of genital skin and mucous membranes are common. Most of these painful disorders are transient and are caused by inflammation from acute genital infection. Acute infections that most commonly cause vulvo-vaginal inflammation include acute episodes of candidiasis, trichomoniasis, genital herpes, furuncles and infection of the greater vestibular glands. The cause of acute inflammation usually is readily discernable by the clinician and treatment usually resolves both the inflammation and the pain. Chronic genital pain is more problematic because the causes are often are difficult to discern. A recent review provides a systematic approach to vulvar disease and offers a comprehensive list of diseases to consider [469]. Treatment often does not totally remove pain. In many cases, treatment is not standard and does little to even substantially reduce pain. Unfortunately, iatrogenic inflammation of the vulvar skin is common from self-treatment or contact with irritants. Nearly all women with chronic vulvar symptoms first use over-the-counter anti-fungal medication. However, candida was found by physicians in only one third of such patients. This self treatment may be associated with increased duration of symptoms, which suggests a detrimental effect from the medication [470]. Some chronic genital pain is constant even without intercourse, but intercourse usually causes an exacerbation of the pain, often to the point where intercourse is avoided or stopped totally. Raised vulvar lesions usually do not cause pain but must be accurately diagnosed and treated. 3. VULVAR VESTIBULITIS SYNDROME II. TYPES OF MUCOUS MEMBRANE DISEASE VVS represents one of the most common causes of genital pain and pain with intercourse. Pain usually is noticed with attempted or completed vaginal penetration, although in more severe cases pain will be present with other activity like sitting or running. Besides pain, vulvar burning and itching are common. Together, these symptoms cause physical, sexual and psychological distress [478]. Community studies suggest vulvar pain is common, but the pre- 1. VULVODYNIAS When signs of VVS or other diagnosis are absent, and biopsies and culture is negative, the term dysesthetic vulvodynia is used. Here all the vulval structures are of normal appearance and the woman describes vulvar burning and pain (vulvodynia) severe 953 valence has varied widely from 3-18% [479, 480]. VVS has been described in up to 15% of gynecologic outpatients [481]. VVS was thought to primarily affect Caucasian women [482, 483]. A recent survey of ethnically diverse women gave similar lifetime prevalences of chronic vulvar burning or pain on contact [484]. ment. In fact, as is common for inflammatory conditions, allele 2 of the IL-1ß gene was found in significantly more women with VVS (40%) than controls (25%) [488]. Leukocytes in blood from women with VVS also produce less interleukin-1 receptor antagonist, which suggests a failure in down regulation of inflammation [489]. Allele. 3 of the gene encoding the interleukin-1 receptor antagonist was present in the homozygous form in 53% of women with VVS compared to an 8.5% of control women [490]. Although VVS is easy to diagnose for the experienced clinician, the mean time between the onset of symptoms and diagnosis usually reaches two years or longer. A triad of conditions are necessary to diagnose VVS : 1) pain with penetration or attempted penetration ; 2) tenderness of the vestibular area upon even light touch with a cotton applicator ; and 3) variable erythema of the vestibular area [417]. The areas of allodynia (sensation of pain from light touch stimulus, are typically between 4 and 8 o'clock on the introitus, just exterior to the hymeneal ring but may involve the skin around the openings of the Skene's ducts. However, the whole introital rim may be involved. The area of tenderness, allodynia and erythema can be difficult to locate because they are usually hidden in folds of the vulva - presumably explaining the typical long time between the onset and diagnosis. 3. POSSIBLE ANTIGEN(S) INVOLVED IN VULVAR VESTIBULTIS SYNDROME The presence of a high T-lymphocyte concentration and increased levels of pro-inflammatory mediators point to a chronic immunologic induced inflammatory response to some antigen [491]. The antigen that induced VVS for an individual could still be present in vulvar tissues in a small concentration or the antigen could have stimulated the inflammation, but be gone by the time patients usually present with VVS. The most likely antigen candidate would be from microbes that commonly affect the vulva. Human papilloma virus (HPV) was first considered, but in multiple studies, HPV was as common in controls as women with VVS [492-494]. Herpes simplex virus (HSV) is also a common vulvar infection, but, to date, HSV does not appear to cause VVS [384, 495]. Candida is an antigen present in the vulva more frequently than HPV or HSV. Up to 80% of women develop symptomatic candidiasis during their lifetime. Patients with VVS have a frequent history of candidiasis, often recurrent [496, 497]. A modest prevalence of recovery of candida occurs from women with VVS [498, 499]. Undoubtedly, other microbial antigens from bacteria, viruses or other microbes or non-microbial antigens are present in the environment or in chemicals that come in contact with vulvar skin could also cause VVS. III. ETIOLOGY 1. INFLAMMATION IN VULVAR VESTIBULITIS SYNDROME The etiology of VVS is unknown but VVS may represent a chronic local inflammatory condition with a wide variety of etiologic causes. T-cell lymphocytes make up most of the inflammatory cells present in vulvar biopsies obtained from those with VVS [485, 486]. Plasma cells indicative of ongoing chronic infection are present, but not in large numbers. Mast cells and eosinophils indicative of an allergic condition are less common. The vulvar tissue of patients with VVS contains elevated tissue levels of interleukin I-ß (IL-1) and tumor necrosis factor alpha (TNF-α), but these pro-inflammatory mediators are actually at higher levels in the surrounding vulvar tissue than in the area of inflammation, confirming the clinical finding of a wider area of involvement beyond the area of erythema [487]. Candida is infrequently identified by potassium hydroxide wet mounts, which require about 105 microbes to be positive. Candida frequently is isolated on culture from women with VVS, although extensive comparisons with control groups are lacking [496, 497]. Some patients with chronic recurrent vulvo-vaginitis candidiasis (VVC) are noted to develop VVS when they are prospectively followed. Further, some women relate the onset of VVS to an acute episode of VVC and patients cured of VVS often develop recurrent genital pain when another episode of VVC occurs. 2. GENETICS OF VULVAR VESTIBULITIS SYNDROME Recent work points to a possible genetic involve- 954 mation, more activation of T cells, more adhesion molecule expression (5 in Figure 8) and an increased collection of activated T cells [491]. 4. IMMUNOLOGIC MODEL OF VULVAR VESTIBULITIS SYNDROME The immunologic response that results in cutaneous T lymphocyte cell pathology is well described for other examples of disease with chronic T-lymphocyte infiltration [491]. The innate immune system acts to arrange for cutaneous skin immune surveillance by the identification of antigens in the skin and the translation of antigen signal to memory T lymphocytes. Certain memory T cells contain a cell surface adhesion molecule called cutaneous lymphocyte antigen (CLA). T cells with CLA circulate preferentially in the skin as opposed to circulating to internal organs. Antigens in the vulvar skin initially are identified by dendritic cells with macrophage-like characteristics (see Figure 8). As an example, macromolecules from candida antigens are efficiently internalized by dendritic cells, which, in turn, migrate to the regional lymph node. 5. CLINICAL RELEVANCE OF IMMUNOLOGICAL AND NEUROGENIC INFLAMMATORY THEORIES In this model, it is proposed that repetitive antigen stimulation or the prolonged presence of antigen markedly up-regulates the local inflammation (6 in Figure 9. The presence of a high concentration or a persistence of chronic pro-inflammatory molecules such as IL-1 and TNF-α, but also serotonin, bradykinin and histamine could sensitize local C nerve fibers [500] Inflammation also increases the synthesis of sensory neuropeptides (such as calcitonin gene-related peptide [CGRP] and substance P) from activated C fibers. These substances themselves have a proinflammation effect [501]. Prolonged C fiber firing reduces the threshold of pain and results in hyperalgesia (7 in Figure 9). Further, transport of CGRP and substance P to the dorsal horn of the spinal cord sensitizes cord neurons with the end result that touch is perceived as pain (allodynia). A significant increase in the number of intra-epithelial nerve endings occur in women with VVS compared to controls [384, 388]. The nerve endings appear to be nociceptors [502], and it has been suggested that the erythema results from a neurogenic rather than an inflammatory source [503]. This chronic pain may lead to hypertonicity of the pelvic muscles (8 in Figure 9). The reduced pain threshold and pelvic muscle hypertonicity, in turn, causes more pelvic pain than one might expect otherwise. In the lymph node, dendritic cells meet continuously circulating naive T cells. When a naïve T cell encounters and interacts with the candida antigens in a dendritic cell, it becomes activated. Activation of the T cell in the lymph node produces a memory T cell (see Figure 8) and the expression of CLA provide this cell with the keys that, when it migrates out of the lymph node and into blood, allows it to escape the blood and circulate only in skin. Thus, activated T cells have the molecular keys that allow their exit from the blood through the vascular endothelium in skin (3 in Figure 8). The adhesion molecule property of CLA allows tethering to occur of activated memory CLA-positive T cells traveling in post capillary venules to the endothelium of these venules. The specific venule is identified by the expression of intracellular adhesion molecules and vascular-cell adhesion molecules on the inner endothelial surface. These adhesion molecules tether and slow travel of the T cell in the venule, which allows it to slide between endothelial cells into the local skin tissue [491]. The adhesion molecules are expressed in the endothelial cells by the action of nuclear factor-kß (NF-kß) which is formed in the local skin. The identification of antigens such as candida by dendritic cells and especially by activated T cells produces IL-1 and TNF-a, which, in turn, activate the NF-kß pathway. The persistence of candida or any antigen in the skin further activates memory CLA T cells and produces a further acceleration in the production of IL-1 and TNF-α (4 in Figure 8). The IL-1 and TNF-α signal produces even more NFkß results in a circle effect of even more local inflam- It is unclear why surgery improves the local pain and decreases pain with intercourse in some subjects with VVS, but it is possible that surgery removes the target tissue of skin containing pro-inflammatory molecules and the local vascular epithelium to which CLA T-cells home. W. MANAGEMENT OF SEXUAL PAIN DISORDERS I. GENERAL REMARKS Sexual pain disorders are heterogeneous, multisystemic and multifactorial disorders that should be trea- 955 Figure 8. Immunological model of vulvar vestibulitis FIgure 9 . Immunological model of vulvar vestibulitis cont. 956 ted in a multimodal way according to etiological factors, risk profile and context. The following algorithm with three distinctive characteristics meets these requirements. II. THERAPEUTIC OPTIONS In table 34 the various treatment modalities for VVS are presented by area. 1. GENERAL RECOMMENDATIONS 1. MEDICAL INTERVENTION 1. A multidimensional and multidisciplinary approach with specific attention to 6 areas : the mucous membrane, the pelvic floor, the experience of pain, sex & partner therapy, the emotional profile and genital mutilation/sexual abuse (Table 34). There is no “one size fits all” approach and no “oror” approach but an “and-and” approach. On medical intervention for VVS there are only two published studies that are methodologically correct (level 2) : Fluconazole, Cromolyn [505, 506]. Both interventions proved to be no more effective than placebo. One confounding factor is a consistent improvement of 20-30% of patients with VVS when treated with placebo or with no therapy [506]. In spite of this, many clinicians continue to include in their biopsychosexual therapeutic approaches, medical interventions of unknown efficacy. Unless part of a RCT, it is recommended that topical medication be restricted to inert creams. (Possibly repeated touch at sub threshold pain levels provides therapeutic benefit). 2. Individualized treatment After careful listening to her story and after she has been well informed about the illness and its natural course and possible treatments or ways of handling it, a treatment plan is made. 3. Patient focused approach: it is up to the woman and her partner to decide which treatment they wish to embark on. If the careful assessment of psychological function has shown some psychopathology, this should be treated first with psychotherapy. By involving the women in the decision process, regarding the specific treatment of the pain, they share the responsibility for treatment choice and this is known to have a positive effect on the treatment outcome [504]. Shifts in preference for a certain approach will depend on the country in question, women's attitudes regarding psychosexual therapy versus surgery, individual health care systems, cost effectiveness of the various modalities, e.g. for VVS - surgery, cognitive behavioral therapy, biofeedback, or combination. Tricyclic anti-depressants, venlafaxine, anticonvulsants - usually carbamazepine or gabapentin offer some pain relief, although total pain resolution with these drugs appears infrequent (level 3b). The starting dose of nortriptyline and other tricyclic antidepressants is low, 10mg, but can be gradually increased to 40-60mg daily as tolerated. Similar doses used to treat essential (dysesthetic) vulvodynia [336] have augmented the treatment of the pain in women with VVS [410]. 2. HYGIENE MEASURES Preventive hygienic measures (level 5) include no soap, no vaginal douching, no nylon underwear (“ventilation”), no pantyliner (mini pads), fluids to produce 1500 ml urine daily and toilet hygiene. Hydration with sitz baths may help reduce inflammation and symptoms. 2. A COUNSELING MODEL This approach implies that the health care provider has to be familiar with the counseling model. He or she is advisor and counselor and takes care that the woman is in full command of the situation. This is a treatment that is very time-consuming, requires great patience, great empathy, sensitivity to non-verbal signals and insight into relational interactions. He or she must be able to identify the woman's ambivalent feelings regarding coitus, sex, her partner, her own body, her desire to have children. He or she must be able to bring to light serious relational problems or severe traumatic experiences (sexual violence) and he or she has to realise that being able to have sex does not automatically mean that the coitus is enjoyed. It is highly recommended that the health care provider receives suitable training. 3. RECOMMENDATIONS (LEVEL 5) RE SEXUAL ACTIVITY For protection of the mucous membrane no vulvar penetration with penis, finger or tongue should be advised and no semen in the vulva. Some women feel very guilty and some men feel very frustrated about this. Persistent lack of sexual desire in spite of significant improvement in sexual frequency has been observed [447]. Therefore normalizing, reframing and encouragement of non-penetrative sex is needed since healing usually takes many months. It is recommended the couple aim at pleasurable and 957 Table 34 : Algorithm of management of sexual pain disorders 958 relaxing sex (with orgasms for both partners as desired) without guilt feelings for the woman and without negative sexual tension for the man. 4. VAGINAL EMG FLOOR X. CONCLUSIONS RE SEXUAL PAIN BIOFEEDBACK, PELVIC PHYSICAL THERAPY, COGNITIVE I. NEUROLOGICAL MECHANISMS BEHAVIORAL THERAPY AND VESTIBULECTOMY There is preliminary information to suggest that vaginal EMG biofeedback, pelvic floor physical therapy, cognitive behavioral therapy and vestibulectomy may all be useful interventions for VVS (level 2b-4b) [444-447]. Treatment results are very similar. This may indicate a non-specific treatment effect in terms of attention, validation of her pain, and the patient's feeling of control and competence. The active constituents seem to be effective on a meta level rather than on a content level : how you are doing it, may be more important than what you are doing. This phenomenon deserves further study. 5. PROGNOSTIC VVS From this database, the following recommendations can be drawn with regard to the role of neurological factors in the etiology (causation and/or maintenance) of distinct sexual pain disorders: From animal studies and clinical observations there is increasing evidence for the role of neuropathic pain mechanisms (neurogenic inflammation, peripheral sensitization, sensitized nociceptors, primary hyperalgesia, and central sensitization) in the pathophysiology of sexual pain disorders. More basic research in this field is needed. In clinical research the use of a diagnostic tool capable of differentiating among women with different types of genital pain, quantifying the severity of the pain and changes of the pain as a result of treatment is highly recommended. FACTORS AND SURGERY FOR A detailed recent critique of gynecological/surgical procedures for VVS suggest the following indicate better prognosis [507] : II. PSYCHOLOGICAL FACTORS a. Lack of any characteristics of vaginismus before the surgery With regard to the role of psychological factors in the possible etiology (causation and/or maintenance) of distinct sexual pain disorders the following recommendations can be drawn : b. Acquired rather than lifelong introital dyspareunia c. Very small amount of surface area involved with allodynia d. Lack of involvement of the Skene duct openings Empirical literature has demonstrated the comorbid presence of clinical psychopathology in the sexual pain disorders. The pervasiveness of clinical psychopathology warrants careful assessment of clinically relevant depression and anxiety disorders for the purpose of treatment planning. e. Lack of vulvodynia, i.e. only introital dyspareunia f. Willingness to have sex therapy if offered. One problem with many of the studies in this review is that the follow-up was short term or unspecified. Clinical experience is that benefit from surgery is often temporary with symptoms returning at about 18-36 months. However, longer follow-up with remaining good outcome is reported by some investigators [508-510]. The role of psychopathology and of attentional and cognitive processes in the etiology of dyspareunia generally and VVS was demonstrated in controlled studies, although these findings await replication. Psychological etiological factors underlying vaginismus are unresolved. Women with VVS demonstrate attentional bias for pain-related stimuli (thermal and tactile stimulation) as compared with normal controls, and lowered sensitivity to pain than asymptomatic women. This lowered sensitivity is not limited to the genital area, 959 is stable over time and the level of hypervigilence is largely accounted for by state and trait anxiety levels. These experimental findings need replication. Also impairment of genital responding in women with dyspareunia by specific sexual stimulation (audiovisual representation of penile-vaginal intercourse) during laboratory investigation needs replication. 6. that there is accumulating basic research to support the idea that the pelvic floor musculature, like other muscle groups is indirectly innervated by the limbic system and therefore highly reactive to emotional stimuli and states and 7. that pelvic floor focused therapies for dyspareunia may be effective. Psychosocial variables predictive for better outcome in women with VVS were higher socioeconomic status, lower education, and childlessness. Willingness to be psychologically evaluated was highly predictive for positive outcome of limited vestibulectomy, as was cooperation of patient in postoperative counseling, localized disease, acquired vs. lifelong symptoms, absence of vulvodynia and non-involvement of Skene duct openings. Prediction of treatment by means of psychological or psychosocial variables has not been investigated in dyspareunia not stated to be due to vestibulitis. Prediction of treatment by means of psychological or psychosocial variables has been investigated in vaginismus but the three studies were non-controlled. More prospective research with special attention for predictor variables is needed. IV. DEFINITIONS RE SEXUAL PAIN It is recommended that definitions of vaginismus and dyspareunia are revised, as in the recent consensus paper [64] and further modified as knowledge of the underlying pathophysiological mechanisms increases. Also, vaginismus and dyspareunia should not be characterized as simply “disorders of the pelvic floor” or as a “pain problem” or as a “vestibulum problem” or as “psychological problem”. It is obvious that current diagnostic categories may overlap, and need to be reconceptualized. Symptoms may be cause as well as effect of the complaints. For treatment an integrated approach is recommended. III. PELVIC FLOOR FACTORS V. TREATMENT With regard to the role of the pelvic floor in the etiology (causation and/or maintenance) of distinct sexual pain disorders : Consistent level 2 studies reveal The treatment of vulvar vestibulitis with EMG biofeedback, pelvic floor physical therapy, cognitive behavioral therapy and vestibulectomy has been evaluated to be effective. Significant improvement in experienced pain, and in intercourse frequency and other measures of sexual functioning is reported. Results were found to be maintained over time. Irrespective of the kind of treatment, the results are very similar. This indicates a non-specific treatment effect that could be specified as a “patient centered approach”. In future research this non-specific treatment aspect has to be validated. 1. that differentiation between vaginismus and dyspareunia using clinical tools is difficult, or nearly impossible ; 2. that vaginal spasms have not been identified ; 3. that only physical therapists can differentiate vaginismic women from matched controls based on muscle tone or strength differences ; 4. that despite strong clinical support for the treatment the traditional treatment of vaginismus with vaginal “dilatation” plus psycho-education, desensitization etc., it is not to date supported by scientific study. Controlled studies are needed to test promising interventions. VI. RECOMMENDATIONS FOR CLINICAL PRACTICE 5. that there does appear some indication that pelvic floor muscle tone and strength measures for women suffering from VVS are intermediate between those of women with vaginismus and no pain controls, The examination technique to search for the cause of dyspareunia is more detailed and requires much 960 That approximately 15% of younger women have chronic dyspareunia that is poorly understood and for which cure is infrequent, makes this an urgent health issue. Unlike complaints of “low desire/low interest”, the vast majority of women with chronic dyspareunia see it as hugely problematic and distressing. Despite this distress, and the persistent repeated requests for help from some women, the total lack of request for help by many others also deserves study. more finesse than a routine pelvic examination. If the medical examination is conducted correctly, it can be highly therapeutic. Such an examination can best be referred to as an “educational gynecological sexological examination”. The use of brief personality and psychological questionnaires is advocated because they could be of interest to detect possible co morbidity, for tailoring treatment and to evaluate the effect of the treatment. The degree of pain should be documented and the use of the vulvalgesiometer is recommended. Abusive experiences of many types leave long-term sexual sequelae, the optimal management of which is unclear. Clearly, a focus on prevention is vital. It is recommended that the whole area of prevention of sexual pain by education re sexuality be addressed. The contextual nature of women's sexuality and the importance of the subjective over the physical experience strongly supports the need for biopsychosocial assessment of sexual dysfunction and similarly an integrated treatment. Given the comorbidity of women's sexual dysfunctions, despite the inherent complexity, future research would merit focusing on this comorbidity as well as a biopsychosocial approach. Y. CONCLUSIONS TO CHAPTER Much of the research reviewed in this chapter is based on assumptions about women's sexual function which are not supported by clinical and empirical data. The past focus on assessing and treating apparent lack of genital congestion may now change to attempting to understand the disconnection from/inattention to, the genital events, which do occur promptly in response to sexual stimulation in most women complaining of lack of arousal. An emphasis on analysis of the emotions and thoughts engendered by that sexual stimulation is needed, given both are known to strongly influence the woman's subjective experience of arousal. Better understanding of genital vasocongestion and its disruption in the small subgroup of women with genital arousal disorder is expected from delineation of the autonomic innervation of the genitalia and the identification of the neurotransmitters involved in vaginal smooth muscle relaxation. REFERENCES The focus on assessing and attempting to change a woman's frequency of apparently spontaneous sexual thoughts, fantasies and desire for sex is now strongly challenged by the evidence that many sexually satisfied women in longer term relationships rarely experience these traditional markers of sexual desire. There is evidence of a very broad normative range. Moreover, sexual desire is not the reason usually given for women's agreeing to or instigating sexual activity. Thus, an understanding of why there may be few or no reasons/incentives or interest for a sexual experience, becomes the focus worthy of future study. 1. FUGL-MEYER AR, SJÖGREN FUGL-MEYER K. Sexual disabilities, problems and satisfaction in 18 to 74-year-old Swedes. Scand J Sexology 1999;2(2):79-105. 2. LAUMANN EL, PAIK A, ROSEN RC. Sexual dysfunction in United States: Prevalence and predictors. JAMA 1999;10:537545. 3. SJÖGREN FUGL-MEYER K. On categorization and quantification of women's sexual dysfunctions. An epidemiological approach. Int J Impot Sexual Med 2003. In press. 4. BANCROFT J, LOFTUS J, LONG JS. Distress about sex: A national survey of women in heterosexual relationships. Arch Sex Behav 2003;32:193-211. 5. DUNN KM, CROFT PR, HACKETT GI. Sexual problems: The study of the prevalence and need for health care in the general population. J Epidemiol Community Health 1999;53:144-148. 6. ZORZON M, ZIVADINOV R, BOSCO A, BRAGADIN LM, MORETTI R, BONFIGLI L, MORASSI P, IONA LG, CAZZATO G. Sexual dysfunction in multiple sclerosis: A casecontrol study. I. Frequency of comparison groups. Mult Scler 1999;5(6):418-427. 7. KENNEDY SH, EISFELD BS, DICKENS SE, BACCHIOCHI JR, BAGBY RM. Antidepressant induced sexual dysfunction during treatment with moclobemide paroxetine, sertraline and venlafaxine. J Clin Psychiatry 2000;61:276-281. 8. BERGMARK K, AVALL-LUNDQVIST E, DICKMAN PW, HENNINGSOHN L, STEINECK G. Vaginal changes and sexuality in women with a history of cervical cancer. N Engl J Med 1999;340:1383-1389. 9. ENZLIN P, MATHIEU C, VAN DENBRUEL A, BOSTEELS J, VANDERSCHUEREN D, DENYTTENAERE K. Sexual dysfunction in women with type 1 diabetes. Diabetes Care 2002;25(4):672-677. 10. BARBER M, VISCO AG, WYMAN JF, FANTL JA, BUMP RC. Sexual function in women with urinary incontinence in pel- 961 33. DENNERSTEIN L, LEHERT P, BURGER H, DUDLEY E. Factors affecting sexual functioning of women in the midlife years. Climacteric 1999;2:254-262. vic organ prolapse. Obstet Gynecol 2002;99:281-289. 11. BANCROFT J. The medicalization of female sexual dysfunction: the need for caution. Arch Sex Behav 2002;31(5):451-455. 34. WYLIE KR, STEWARD D, SEIVEWRIGHT N, SMITH D, WALTERS S. Prevalence of sexual dysfunction in three psychiatric outpatient's settings: A drug misuse service, an alcohol misuse service and a general adult psychiatry clinic. Sex Relationship Ther 2002;17(2):149-160. 12. ÖBERG K, SJÖGREN FUGL-MEYER KS, FUGL-MEYER AR. On sexual well-being in sexually abused Swedish women: epidemiological aspects. Sex Rel Ther 2002;17(4):329-341. 13. BASSON R. Women's sexual desire - disordered or misunderstood. J Sex Marital Ther 2002;28S:17-28. 35. BASSON R, MCINNES R, SMITH MD, HODGSON G, KOPPIKER N. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal. Gend Based Med 2002;11(4):367-377. 14. MASTERS WH, JOHNSON V. Human sexual response. Boston: Little, Brown & Co.; 1966. 15. KAPLAN HS. Disorders of Sexual Desire. New York: Brunner Mazel; 1979. 36. CYRANOWSKI JM, ANDERSEN BL. Schemas, sexuality, romantic attachment. J Pers Soc Psychol 1998;74(5):1364-1379. 16. LUNDE I, LARSON GK, FOG E, GARDE K. Sexual desire, orgasm, and sexual fantasies: A study of 625 Danish women born in 1910, 1936 and 1958. J Sex Educ Ther 1991;17:111-115. 37. DEROGATIS LR, SCHMIDT CW, FAGAN PJ, WISE TN. Subtypes of anorgasmia via mathematical taxonomy. Psychosomatics 1989;30(2):166-173. 17. HILL CA, PRESTON LK. Individual differences in the experience of sexual motivation: Theory and measurement of dispositional sexual motives. J Sex Res 1996;33(1):27-45. 38. SEGRAVES KB, SEGRAVES RT. Hypoactive sexual desire disorder: Prevalence and comorbidity in 906 subjects. J Sex Marital Ther 1991;17(1):55-58. 39. ROSEN RT, TAYLOR JF, LEIBLUM SR. Prevalence of sexual dysfunction in women: Results of a survey study of 329 women in an outpatient gynecological clinic. J Sex Marital Ther 1993;19:171. 40. MESTON CM. Validation of the female sexual function index (FSFI) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder. J Sex Marital Ther 2003;29:39-46. 41. TRUDEL G, RAVART M, MATTE B. The use of the multi axis diagnostic system for sexual dysfunctions in the assessment of hypoactive sexual desire. J Sex Marital Ther 1993;19(2):123130. 42. MOROKOFF PJ, HEIMAN JR. Effects of erotic stimuli on sexually functional and dysfunctional women: Multiple measures before and after sex therapy. Behav Res Ther 1980;18:127-137. 43. BROTTO L, BASSON R, GORZALCA B. Psychophysiological assessment in premenopausal sexual arousal disorder. Journal of Sexual Medicine. (in press) 44. BEGGS VE, CALHOUN LS, WOLCHIK SA. Sexual anxiety and female sexual arousal: A comparison of arousal during sexual anxiety stimuli and sexual pleasure stimuli. Arch Sex Behav 1987;16:311-319. 45. MESTON CM, HEIMAN JR. Ephedrine-activated physiological sexual arousal in women. Arch Gen Psychiatry 1998;55:652656. 46. MESTON CM, GORZALKA BB. The effects of immediate, delayed and residual sympathetic activation on physiological and subjective sexual arousal in women. Behav Res Ther 1996;34:143-148. 47. BROTTO L, GORZALKA B. Genital and subjective sexual arousal in postmenopausal women: Influence of laboratory induced hyperventilation. J Sex Mar Ther 2002;28S:39-53. 48. LAAN E, EVERAERD W, VAN BELLEN G, HANEWALD G. Women's sexual and emotional responses to male- and femaleproduced erotica. Arch Sex Behav 1994;23(2):153-169. 49. LAAN E, EVERAERD W, VAN DER VELDE J, GEER JH. Determinants of subjective experience of sexual arousal in women: Feedback from genital arousal and erotic stimulus content. Psychophysiology 1995;32:444-451. 50. MESTON CM, WORCEL M. The effects of yohimbine plus Larginine glutamate on sexual arousal in postmenopausal women with sexual arousal disorder. Arch Sex Behav 2002;31(4):323332. 51. BECK JG, BOZMAN AW. Gender differences in sexual desire: The effects of anger and anxiety. Arch Sex Behav 1995;24(6):595-612. 18. GALYER KT, CONAGLEN HM. HARE A, CONAGLEN JV. The effect of gynecological surgery on sexual desire. J Sex Marital Ther 1999;25:81-88. 19. SCHULTZ WCM, VAN DE WIEL HBM, HAHN DEE. Psychosexual functioning after treatment for gynecological cancer and integrated model, review of determinant factors and clinical guidelines. Int J Gynecol Cancer 1992;2:281-290. 20. REGAN P, BERSCHEID E. Belief about the states, goals and objects of sexual desire. J Sex Marital Ther 1996;22:110-120. 21. KLUSMANN D. Sexual motivation and the duration of partnership. Arch Sex Behav 2002;31(3):275-287. 22. CAWOOD EHH, BANCROFT J. Steroid hormones, the menopause, sexuality and well being of women. Psychol Med 1996;26:925-936. 23. GARDE K, LUNDE I. Female sexual behaviour. The study in a random sample of 40-year-old women. Maturitas 1980;2:225240. 24. SHOKROLLAHI P, MIRMOHAMADI M, MEHRABI F, BABAEI G. Prevalence of sexual dysfunction in women seeking services at Family Planning Centres in Tehran. J Sex Marital Ther 1999;25:211-215. 25. NAPPI R, VENERONI F, VERDE JB, POLATTI F, FIGNON A, FARINA C, GENAZZANI AR. Climacteric complaints, female identity, and sexual dysfunctions. J Sex Marital Ther 2001;27:567-576. 26. ERNST C, FÖLDÉNYI M, ANGST J. The Zurich study: XXI Sexual dysfunctions and disturbances in young adults. Eur Arch Psychiatry Clin Neurosci 1993;243:170-188. 27. SPRECHER S. Sexual satisfaction in premarital relationships: Associations with satisfaction, love, commitment, and stability. J Sex Res 2002;39(3):190-196. 28. NUSBAUM MRH, GAMBLE G, SKINNER, B, HEIMAN J. The high prevalence of sexual concerns amongst women seeking routine gynecological care. Fam Pract 2000;49(3):229-232. 29. SJÖGREN FUGL-MEYER K, FUGL-MEYER AR. Sexual disabilities are not singularities. Int J Impot Res 2002;14:487493. 30. FUGL-MEYER KS. Erectile problems - the perspective of the female. Scand J Urol Nephrol 1998;32:S197-S212. 31. HARTMANN U, HEISER K, RÜFFER-HESSE C. KLOTH G. Female sexual desire disorders: Subtypes, classification, personality factors, a new direction for treatment. World J Urol 2002;20:79-88. 32. HILL CA. Gender, relationship stage, and sexual behaviour: The importance of partner emotional investment within specific situations. J Sex Res 2002;39(3):228-240. 962 Sexual behaviour in Britain. The national survey of sexual attitudes and lifestyles. London: Penguin Books; 1994. 52. KATZ RC, GIPSON MT, TURNER S. Brief report: Recent findings on the sexual aversion scale. J Sex Marital Ther 1992;18(2):141-146. 72. DENNERSTEIN L, RANDOLPH J, TAFFE J, DUDLEY E, BURGER H. Hormones, mood, sexuality, and the menopausal transition. Fertil Steril 2002;77:S42-S48. 53. LAAN E, EVERAERD W. Determinants of female sexual arousal: Psychophysiological theorian data. Annu Rev Sex Res 1995;6:32-76. 73. BASSON R. The female sexual response: The role of drugs in the management of sexual dysfunction. Obstet Gynecol 2001;98:350-353. 54. LAAN E, VAN DRIEL E, VAN LUNSEN RHW. Seksuele reakties van vrouwen met een seksuele opwindingsstoornis op visuele seksuele stimuli [Sexual responses of women with sexual arousal disorder to visual sexual stimuli]. Tijdschrift voor Seksuologie 2003;27:1-13. (Also submitted to Am J Psychiatry) 74. QUIRK FH, HEIMAN JR, ROSEN RC, LAAN E, SMITH MD, BOOLEL M. Development of a sexual function questionnaire for clinical trials of female sexual dysfunction. J Women's Health Gend Based Med 2002;11(3):277-289. 55. REISSING ED, BINIK YM, KHALIFÉ S, COHEN D, AMSEL R. Vaginal spasm, pain and behaviour: An empirical investigation of the diagnosis of vaginismus. Arch Sex Behav. In press. 75. TAYLOR JF, ROSEN RC, LEIBLUM SR. Self-report assessment of female sexual functioning: Psychometic evaluation of the brief index of sexual function for women. Arch Sex Behav 1994;23:627-642. 56. WORLD HEALTH ORGANIZATION. The ICD-10 classification of mental and behavioral disorders: Clinical descriptions and diagnostic guidelines. Geneva, Switzerland; 1992. 76. DEROGATIS LR. The Derogatis interview for sexual functioning (DISF/DISF-SR): An introductory report. J Sex Marital Ther 1997;231:291-304. 57. AMERICAN PSYCHIATRIC ASSOCIATION DSM-IVTR. Diagnostic and Statistical Manual for Mental Disorders, 4th Ed. Washington, DC: American Psychiatric Press, 2000. 77. ROSEN R, BROWN C, HEIMAN J, LEIBLUM S, MESTON, SHABSIGH R, FERGUSON D, D'AGOSTINO, JR. R. Female Sexual Function Index (FSFI): A multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000;26:191-208. 58. BASSON R. Human sex response cycles. J Sex Marital Ther 2001;27(1):33-43. 59. LEVIN RJ. Sexual desire and the deconstruction and reconstruction of the human female sexual response model of Masters and Johnson. In: Everaerd W, Laan, Both S (eds). Sexual appetite, desire and motivation: energetics of the sexual system. Amsterdam: The Royal Netherlands Academy of Arts and Sciences; 2000. 78. WOUDA J, HARTMAN P, BAKKER R, BAKKER JO, VAN DE WIEL HBM, WEIJMAR SCHULTZ WCM. Vaginal plethysmography in women with dyspareunia. J Sex Res 1998;35:141-147. 60. TOLMAN DL, DIAMOND LM. Desegregating sexuality research: Cultural and biological perspectives on gender and desire. Annu Rev Sex Res 2001;12:33-74. 79. LAAN E, EVERAERD W, VAN AANHOLD MT, REBEL M. Performance demand and sexual arousal in women. Behav Res Ther 1993;31(1):25-35. 61. BASSON R. Rethinking low sexual desire in women. BJOG 2002;109:357-363. 80. LAAN E, EVERAERD W, 1995. Habituation of female sexual arousal to slides and film. Arch Sex Behav 1995;24(5):517-541. 62. EVERAERD W, LAAN E, BOTH S, VAN DER VELDE J. Female sexuality. In: Szuchman LT, Muscarella F (eds). Psychological perspectives of human sexuality. New York: John Wiley & Sons Inc.; 2000. 81. BURNETT AI, CALVIN TC, SILVER RI, PEPAS DS, DOCIMO SG. Immuno-chemical description of nitric oxide synthase isoforms in human clitoris. J Urol 1997;158(75):278. 82. HOYLE CH, STONES RW, ROBSON T, WHITLEY K, BURNSTOCK G. Innervation of vasculature and microvasculature of the human vagina by NOS and neuropeptide-containing nerves. J Anat 1996;188:633-644. 63. EVERAERD W, LAAN E. Desire for passion: Energetics of sexual response. J Sex Marital Ther 1995;21:255-263. 64. BASSON R, LEIBLUM S. BROTTO L., DEROGATIS L., FOURCROY J., FUGL-MEYER K. et al. Definitions of women's sexual dysfunction reconsidered: Advocating expansion and revision. J Psychosom Obstet Gynaecol. 2003;24:221229 83. OTTESEN B, PEDERSEN B, NEILSEN J, DALGAARD D, WAGNER G, FAHRENKRUG J. Vasoactive intestinal polypeptide (VIP) provokes vaginal lubrication in normal women. Peptides 1987;8:797-800. 65. BÉJIN A. Sexual pleasures, dysfunctions, fantasies and satisfaction. In: Spiral A, Banjos N (eds). ACSF Group. Sexual behaviour and AIDS. Aldershot: Amesbury, 1994. 84. ZIESSEN T, MONCADA S, CELLEK S. Characterization of the non-nitrergic NANC relaxation responses in the rabbit vaginal wall. Brit J Pharmacol 2002;135:546-554. 66. KONTULA O, HAAVIO-MANNILA E. Sexual pleasures. Enhancement of sex life in Finland. Aldershot: Dartmouth; 1995:1971-1992. 85. LEVIN RJ. The physiology of sexual function in women. Clin Obstet Gynecol 1980;7:213-252. 86. MESTON CM, GORZALKA BB. The effects of sympathetic activation on physiological and subjective arousal in women. Behav Res Ther 1995;33:651-664. 67. HAWTON K, GATH D, DAY A. Sexual function in a community sample of middle-aged women with partners. Effects of age, marital, socio-economics, psychiatric, gynecological and menopausal factors. Arch Sex Behav 1994;23:375-395. 87 68. VENTEGODT S. Sex and the quality of life in Denmark. Arch Sex Behav 1998;27:295-307. 69. FISHER WA, BORODITSKY R, BRIDGES M. Measures of sexual and reproductive health among Canadian women. Can J Human Sexuality 1999;8(3):175-182. DELIGANIS AV, MARAVILLA KR, HEIMAN JR, CARTER WO, GARLAND PA, PETERSON BT, HACKBERT L, CAO Y, WEISSKOFF RM. Female genitalia: dynamic MR imaging with use of MS-325 initial experiences evaluating female sexual response. Radiology 2002;225:791-799. 88. BASSON R, BROTTO L. Sexual psychophysiology and effects of sildenafil citrate in estrogenized women with acquired genital arousal disorder and impaired orgasm. BJOG 2003;110:1-11. 70. GOLDSTADT R, BRIGANTI E, TRAN J, WOLFE R, DAVIS SR. Transdermal testosterone therapy improves well being, mood and sexual function in pre-menopausal women. Menopause 2003;10(5):390-398. 89. KARAMA S, LECOURS AR, LEROUX JM, BOURGOUIN P, BEAUDOIN G, JOUBERT S, BEAUREGARD M. Areas of brain activation in males and females during viewing of erotic film excerpts. Hum Brain Mapp 2002;16:1-13. 71. WELLINGS K, FIELD J, JOHNSON AM, WORDSWORTH J. 963 90. DEGROAT WC. Neural control of the urinary bladder and sexual organs. In: Mathias JJ and Bannister R, (eds). Autonomic failure: A textbook of clinical disorders of the autonomic nervous system, 4th Ed. New York: Oxford University Press; 1999. 111. VAN MINNEN A, KAMPMAN M. The interaction between anxiety and sexual functioning: A controlled study of sexual functioning in women with anxiety disorders. Sex Rel Ther 2000;15:47-57. 91. LEVIN RJ, MACDONAGH RP. Increased vaginal blood flow induced by implant electrical stimulation of sacral anterior routes in conscious women: A case study. Arch Sex Behav 1993;22:471-475. 112. AKSARAY G, YELKEN B, KAPTANOGLU C, OFLU S, OZALTIN M. Sexuality in women with obsessive compulsive disorder. J Sex Marital Ther 2001;27:273-277. 113. LEARY MR, DOBBINS SE. Social anxiety, sexual behavior, and contraceptive use. J Pers Soc Psychol 1983;45:1347-1354. 92. SIPSKI ML, ALEXANDER CJ, ROSEN R. Sexual arousal and orgasm in women: Effects of spinal cord injury. Annu Neurol 2001;49:35-44. 114. FIGUEIRA I, POSSIDENTE E, MARQUES C, HAYES K. Sexual dysfunction: A neglected complication of panic disorder and social phobia. Arch Sex Behav 2001;30:369-377. 93. TRAISH AM, MOORELAND RB, HUANG YH, GOLDSTEIN I. Expression of functional a2 adrenergic receptor subtypes in human corpus cavernosum and in culture trabecular smooth muscle cells. J Recept Signal Transduct Res 1997;7:55-67. 115. BODINGER L, HERMESH H, AIZENBERG D, VALEVSKI A, MAROM S, SHILOH R, GOTHELF D, ZEMISHLANY Z, WEIZMAN A. Sexual function and behavior in social phobia. J Clin Psychiatry 2002;63:874-879. 94. MENDELSOHN ME, KARAS RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801-1811. 116. VAN DEN HOUT M, BARLOW D. Attention, arousal and expectancies in anxiety and sexual disorders. J Affect Disord 2000:61:241-256. 95. DEROGATIS LR, MEYER JK, KING KM. Psychopathology in individuals with sexual dysfunction. Am J Psychiatry 1981;138:757-763. 117. COOPER AJ. Some personality factors in frigidity. J Psychosom Res 1969;13:149-155. 96. SCHREINER-ENGEL P, SCHIAVI RC. Lifetime psychopathology in individuals with low sexual desire. J Nerv Ment Dis 1986;174:646-651. 118. DEROGATIS LR, MEYER JK. A psychological profile of the sexual dysfunctions. Arch Sex Behav 1979;8:201-223. 119. KAPLAN HS, FYER AJ, NOVICK A. The treatment of sexual phobias: The combined use of antipanic medication and sex therapy. J Sex Marital Ther 1982;8:3-28. 97. FAGAN PJ, SCHMIDT CW JR, WISE TN, DEROGATIS LR. Sexual dysfunction and dual psychiatric diagnoses. Compr Psychiatry 1988;29:278-284. 98 120. HOON PW, WINCZE JP, HOON EF. A test of reciprocal inhibition: Are anxiety and sexual arousal in women mutually inhibitory? J Abnormal Psychol 1977;86:65-74. OSBORN M, HAWTON K, GATH D. Sexual dysfunction among middle aged women in the community. Br Med J 1988;296:959-962. 121. PALACE EM, GORZALKA BB. The enhancing effects of anxiety on arousal in sexually dysfunctional and functional women. J Abnormal Psychol 1990;99:403-411. 99. CATALAN J, HAWTON K, DAY A. Couples referred to a sexual dysfunction clinic. Psychological and physical morbidity. Br J Psychiatry 1990;156:61-67. 122. PALACE EM. A cognitive-physiological process model of sexual arousal and response. Clin Psychol Sci Pract 1995a;2:370-384. 100. DONAHEY K, CARROLL RA. Gender differences in factors associated with hypoactive sexual desire. J Sex Marital Ther 1993;19:25-40. 123. PALACE EM. Modification of dysfunctional patterns of sexual response through autonomic arousal and false physiological feedback. J Consult Clin Psychol 1995b;63:604-615. 101. VAN LANKVELD JJDM, GROTJOHANN Y. Psychiatric comorbidity in heterosexual couples with sexual dysfunction assessed with the composite international diagnostic interview. Arch Sex Behav 2000;29:479-498. 102. BARLOW DH. Anxiety and its disorders: The nature and treatment of anxiety and panic. New York: Guilford Press; 1988. 103. KAPLAN HS. The new sex therapy: Active treatment of sexual dysfunctions. New York: Brunner & Mazel; 1974. 104. NORTON GR, JEHU D. The role of anxiety in sexual dysfunctions: A review. Arch Sex Behav 1984;13:165-183. 105. MURPHY C, SULLIVAN M. Anxiety and self-concept correlates of sexually aversive women. Sexuality and Disability 1981;4:15-26. 106. KAPLAN HS. The sexual desire disorders. New York: Brunner & Mazel; 1995. 107. CAMPILLO GG, BRAVO CS, CARMONA FM, PERALES RD, CALDERON AV. Anxiety and depression levels in women with and without sexual disorders: A comparative study. Rev Mex Psicol 1999;16:17-23. 108. TRUDEL G, LANDRY L, LAROSE Y. LOW SEXUAL DESIRE: The role of anxiety, depression, and marital adjustment. Sex Mar Ther 1997;12:109-113. 124. PALACE EM, GORZALKA BB. Differential patterns of arousal in sexually functional and dysfunctional women: Physiological and subjective components of sexual response. Arch Sex Behav 1992;21:135-159. 125. BECK AT. Depression: Clinical, experimental, and theoretical aspects. New York: Harper and Row; 1967. 126. KIVELA SL, PAHKALA K. Symptoms of depression in old people in Finland. Z Gerontol 1988;21:257-263. 127. CASSIDY WL, FLANAGAN NB, SPELLMAN M, COHEN ME. Clinical observations in manic depressive disease. JAMA 1957;164:1535-1546. 128. DUNNER DL, DWYER T, FIEVE RR. Depressive symptoms in patients with unipolar and bipolar affective disorder. Compr Psychiatry 1976;17:447-451. 129. KENNEDY SH, DICKENS SE, EISFELD BS, BAGBY RM. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord 1999;56:201-208. 130. FROHLICH P, MESTON C. Sexual functioning and self-reported depressive symptoms among college women. J Sex Res 2002;39:321-325. 109. KATZ RC, JARDINE D. The relationship between worry, sexual aversion, and low sexual desire. J Sex Marital Ther 1999;25:293-296. 131. BARTLIK B, KOCSIS JH, LEGERE R, VILLALUZ J, KOSSOY A, GELENBERG AJ. Sexual dysfunction secondary to depressive disorders. J Gend Specif Med 1999;2:52-60. 110. WARE MR, EMMANUEL NP, JOHNSON MR, BRAWMANMINTZER O, KNAPP R, CRAWFORD-HARRISON M, LYDIARD RB. Self-reported sexual dysfunctions in anxiety disorder patients. Psychopharmacol Bull 1996;32:530. 132. FISHER S. The female orgasm. New York: Basic Books; 1973. 133. APT C, HURLBERT DF. The sexual attitudes, behavior, and 964 relationships of women with histrionic personality disorder. J Sex Marital Ther 1994;20:125-133. 134. HURLBERT DF, APT C, WHITE LC. An empirical examination into the sexuality of women with borderline personality disorder. J Sex Marital Ther 1992;18:231-242. 155. SEGRAVES RT, CROFT H, KAVOUSSI R, ASCHER JA, BATEY SR, FOSTER VJ, BOLDEN-WATSON C, METZ A. Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women. J Sex Marital Ther 2001;27:303-316. 135. APT C, HURLBERT DF. The female sensation seeker and marital sexuality. J Sex Marital Ther 1992;18:315-324. 156. HAWTON K. Treatment of sexual dysfunctions by sex therapy and other approaches. Br J Psychiatry 1995;167:307-314. 136. ANDERSON BL, CYRANOWSKI JM. Women's Sexuality: Behaviors, Responses, and Individual Differences. J Consult Clin Psychol 1995;63:891-906. 157. ROSEN RC, LEIBLUM SR. Treatment of sexual disorders in the 1990s: An integrated approach. J Consult Clin Psychol 1995;63:877-890. 137. COSTA PT, FAGAN PJ, PIEDMONT RL, PONTICAS Y, WISE TN. The five-factor model of personality and sexual functioning in outpatient men and women. Psychiatr Med 1992; 10:199-215. 158. HAWTON K, CATALAN J. Prognostic factors in sex therapy. Behav Res Ther 1986;24:377-385. 159. WHITEHEAD A, MATHEWS A. Factors related to successful outcome in the treatment of sexually unresponsive women. Psychol Med 1986;16:373-378. 138. ANDERSON BL, CYRANOWSKI JM. Women's sexual self schema. J Pers Soc Psychol 1994;67:1079-1100. 160. HAWTON K, CATALAN J, FAGG J. Low sexual desire: Sex therapy results and prognostic factors. Behav Res Ther 1991;29:217-224. 139. MASTERS W, JOHNSON V. Human Sexual Inadequacy, Boston: Little, Brown and Co; 1970. 140. SCHNARCH D. Desire problems: A systemic perspective. Principles and Practice of Sex Therapy, New York: Guilford Press; 2000. 161. BESHARAT MA. Management strategies of sexual dysfunctions. J Contemp Psychother 2001;31:161-180. 162. MILAN RJ JR, KILMANN PR, BOLAND JP. Treatment outcome of secondary orgasmic dysfunction: A two- to six-year follow-up. Arch Sex Behav 1988;17:463-480. 141. HEIMAN JR, MESTON CM. Empirically validated treatment for sexual dysfunction. Ann Rev Sex Res 1997;8:148-194. 142. BASSON R, BERMAN J, BURNETT A, DEROGATIS L, FERGUSON D, FOURCROY J, GOLDSTEIN I, GRAZIOTTIN A, HEIMAN J, LAAN E, LEIBLUM S, PADMANATHAN H, ROSEN R, SEGRAVES K, SEGRAVES RT, SHABSIGH R, SIPSKI M, WAGNER G, WHIPPLE B. Report of the international consensus development conference on female sexual dysfunction: Definitions and classifications. J Urol 2000;163:888-893. 163. HIRST JF, WATSON JP. Therapy for sexual and relationship problems: The effects on outcome of attending as an individual or as a couple. Sex Marital Ther 1997;12:321-337. 164. BERMAN JR, BERMAN LA, TOLER SM, GILL J, HAUGHIE S. Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: A double-blind, placebocontrolled study. J Urol. (2003) 170:2333-2338. 165. CARUSO S, INTELISANO G, LUPO L, AGNELLO C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: A double-blind, crossover, placebo-controlled study. BJOG 2001;108:623-628. 143. LEIBLUM SR. Definition and classification of female sexual disorders. Int J Impot Res 1998;10:S104-S106. 144. SARWER DB, DURLAK JA. A field trial of the effectiveness of behavioral treatment for sexual dysfunctions. J Sex Marital Ther, 1997;23:87-97. 166. SIPSKI ML, ROSEN RC, ALEXANDER CJ, HAMER RM. Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury. Urology 2000;55(6):812-815. 145. LEIBLUM SR, ROSEN RC. Sexual desire disorders. New York: Guilford Press; 1988. 167. KAPLAN SA, REIS RB, KOHN IJ, IKEGUCHI EF, LAOR E, TE AE, MARTINS AC. Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction. Urology 1999;53(3):481-486. 146. CROWE MJ, GILLAN P, GOLOMBOK S. Form and content in the conjoint treatment of sexual dysfunction: a controlled study. Behav Res Ther 1981;19:47-54. 147. ZIMMER D. Does marital therapy enhance the effectiveness of treatment for sexual dysfunction? J Sex Marital Ther 1987;13:193-209. 148. HAWTON K, CATALAN J, MARTIN P, FAGG J. Long-term outcome of sex therapy. Behav Res Ther 1986;24:665-675. 168. CASTELO-BRANCO C, VICENTE JJ, FIGUERAS F, SANJUAN A, MARTINEZ DE OSABA MJ, CASALS E, PONS F, BALASCH J, VANRELL JA. Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Maturitas 2000;34:161-168. 149. HURLBERT DF. A comparative study using orgasm consistency training in the treatment of women reporting hypoactive sexual desire. J Sex Marital Ther 1993;19:41-55. 169. PALACIOS S, MENENDEZ C, JURADO AR, CASTANO R, VARGAS JC. Changes in sex behaviour after menopause: Effects of Tibilone. Maturitas 1995;22:155-166. 150. MCCABE MP. Evaluation of a cognitive behavior therapy program for people with sexual dysfunction. J Sex Marital Ther 2001;27:259-271. 170. NATHORST-BÖÖS J, HAMMAR M. Effects on sexual life--a comparison between tibolone and a continuous estradiol- norethisterone acetate regimen. Maturitas 1997;26:15-20. 151. TRUDEL G, MARCHAND A, RAVART M, AUBIN S, TURGEON L, FORTIER P. The effect of a cognitive behavioral group treatment program on hypoactive sexual desire in women. Sex Rel Ther 2001;16:145-164. 171. LAAN E, VAN LUNSEN RH, EVERAERD W. The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women. Climacteric 2001;4:28-41. 172. KÖKÇÜ A, CETINKAYA MB, YANIK F, ALPER T, MALATYALIOGLU E. The comparison of effects of tibolone and conjugated estrogen medroxy progesterone acetate therapy on sexual performance in postmenopausal women. Maturitas 2000;36:75-80. 152. BASSON R. Low libido in women: Putting treatment in motion. Can J CME 1996;105-110. 153. BASSON RJ. Using a different model for female sexual response to address women's problematic low sexual desire. J Sex Marital Ther 2001;27:395-403. 173. RYMER J, CHAPMAN MG, FOGELMAN I, WILSON POG. A study of the effect of tibolone on the vagina in postmenopausal women. Maturitas 1994;18:127-133. 154. CRENSHAW TL, GOLDBERT JP, STERN WC. Pharmacologic modification of psychosexual dysfunction. J Sex Marital Ther 1987;13:239-252. 174. MENDOZA N, SUÁREZ AM, ÁLAMO F, BARTUAL E, VER- 965 GARA F, HERRUZO A. Lipid effects, effectiveness and acceptability of tibolone vs. transdermic 17 b estradiol for hormonal replacement therapy in women with surgical menopause. Maturitas 2000;37:37-43. 191. ARLT W, CALLIES F, VAN VLIJMEN JC, KOEHLER I, REINCKE M, BIDLINGMAIER M, HUEBLER D, OETTEL M, ERNST M, SCHULTE HM, ALLOLIO B. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Eng J Med 1999;341(14):1013-1020. 175. YOUNG EA, KORSZUN A. The hypothalamic-pituitary-gonadal axis in mood disorders. Endocrinol Metab Clin North Am 2002 31(1):63-78. 192. LØOVÅS K, GEBRE-MEDHIN G, TROVIK TS, FOUGNER K, UHLVING SU, NEDROBØ BG, MYKING OL, KÄMPE O, HUSEBYE ES. Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month randomized parallel group clinical trial. J Clin Endocrinol Metab 2003;88(3):1112-1118. 176. WISNIEWSKI AB, MIGEON CJ, MEYER-BAHLBURG HFL, GEARHART JP, BERKOVITZ GD, BROWN TR, MONEY J. Complete androgen and insensitivity syndrom: Long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab 2000;85:2664-2669. 193. HUNT P, GURNELL E, HUPPERT F. Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000;85:4650-4656. 177. LEIBLUM S, BACHMANN G, KEMMANN E. Vaginal atrophy in the postmenopausal woman: the importance of sexual activity and hormones. JAMA 1983;249:2195-2198. 194. BARNHART K, FREEMAN E, GRISSO JA, RADER DJ, SAMMEL M, KAPOOR S, NESTLER JE. 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(11):3896-3902. 178. NATHORST-BÖÖS J, VON SCHOULTZ H. Psychological reactions and sexual life after hysterectomy with and without oophorectomy. Gynecol Obstet Invest 1992;34:97-101. 179. CONAGLEN HM, CONAGLEN JV. Sexual desire in women presenting for antiandrogen therapy. J Sex Marital Ther 2003;29(4):255-267. 195. BAULIEU E, THOMAS G, LEGRAIN S, ROGER M, DEBUIRE B, FAUCOUNAU V. Dehydroepiandrosterone (DHEA), DHEA sulphate, and aging: Contribution to the DHEAge study to a sociobiomedical issue. Proc Natt Acad Sci 2000;97(8):4279-4284. 180. SHERWIN BB, GELFAND MM, BRENDER W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47(4):339-351. 181. DAVIS SR, MCCLOUD P, STRAUSS BJG, BURGER H Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas 1995;21(3):227-236. 196. GUAY AT, JACOBSON J. Decreased free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) levels in women with decreased libido. J Sex Marital Ther 2002;28 (Suppl 1):129-142. 182. SHIFREN JL, BRAUNSTEIN GD, SIMON JA, CASSON PR, BUSTER JE, REDMOND GP, BURKI RE, GINSBURG ES, ROSEN RC, LEIBLUM SR, CARAMELLI KE, MAZER NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;7;343(10):682-688. 197. GUAY AT. Decreased testosterone in regularly menstruating women with decreased libido: a clinical observation. J Sex Marital Ther 2001;27(5):513-519. 198. TUNGPHAISAL S, CHANDEYING V, SUTTHIJUMROON S, KRISANAPAN O, UDOMRATN P. Postmenopausal sexuality in Thai women. Asia Oceania J Obstet Gynaecol 1991;17(2):143-146. 183. FLOTER A, NATHORST- BÖÖS J, CARLSTROM K, VON SCHOULTZ B. Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well being. Climacteric 2002;5:357-365. 199. SCHREINER-ENGEL P, SCHIAVI RC, WHITE D, GHIZZANI A. Low sexual desire in women: the role of reproductive hormones. Horm Behav 1989;23(2):221-234. 184. DOBS AS, NGUYEN T, PACE C, ROBERTS CP. Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 2002;87(4):1509-1516. 200. ADAMOPOULOS DA, KAMPYLI S, GEORGIACODIS F, KAPOLLA N, ABRAHAMIAN-MICHALAKIS A. Effects of antiandrogen-estrogen treatment on sexual and endocrine parameters in hirsute women. Arch Sex Behav 1988;17(5):421-429. 185. LOBO RA, ROSEN RC, YANG HM, BLOCK B, VAN DER HOOP RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79(6):1341-1352. 201. DAVIS SR, SCHNEIDER HPG, SARTI D, REES M, VAN LUNSEN HW. Androgen levels in normal and oophorectomised women. Presented at the 10th World Congress on the Menopause, Berlin. June 2002 by the Jean Hailes Research Unit. 186. BURGER HG, HAILES J, MENELAUS M. The management of persistent symptoms with estradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 1984;6:351-358. 202. RILEY A, RILEY E. Controlled studies on women presenting with sexual drive disorder: I. Endocrine status. J Sex Marital Ther 2000;26(3):269-283. 187. BURGER HG, HAILES J, NELSON J, MENELAUS M. Effect of combined implants of estradiol and testosterone on libido in postmenopausal women. Br Med J 1987;294:936-937. 203. BANCROFT J, SHERWIN BB, ALEXANDER GM, DAVIDSON DV, WALKER A. Oral Contraceptives androgens and the sexuality of young women: II. The role of androgens. Arch Sex Behav 1991;20:121-135. 188. SARREL P, DOBAY B, WIITA B. Estrogen and estrogenandrogen replacement in postmenopausal women dissatisfied with estrogen-only therapy. sexual behaviour and neuroendocrine response. J Reprod Med 1998;43(10):847-856. 204. REDMOND G, GODWIN AJ, OLSON W, LIPPMAN J. Use of placebo controls in an oral contraceptive trial: Methodological issues and adverse event incidence. Contraception 1999;60:8185. 189. BARRETT-CONNER E. Efficacy and safety of estrogen/androgen therapy: Menopausal symptoms, bone land cardiovascular parameters. J Reprod Med 1998;43:746-752. 205. SANDERS SA, GRAHAM C M, BASS J, BANCROFT J. A prospective study of the effects of oral contraceptives on sexuality and well being and their relationship to discontinuation. Contraception 2001;64:51-58. 190. LABRIE F, BELANGER A, CUSAN L, CANDAS B. Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: Intracrinology. J Clin Endocrinol Metab 1997;82(8):2403-2409. 206. LAUGHLIN GA, BARRETT-CONNOR E, KRITZ-SILVERSTEIN D, VON MUHLEN D. Hysterectomy, oophorectomy 966 life women. In menopause, Lobo RA, Macus R, Kelsey J (eds). San Diego: Academic Press; 2000. P. 170-181. and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab 2000;85(2):645651. 222. CHAKRAVARTI S, COLLINS WP, THOM MW, STUDD JWW. Relation between plasma hormone profiles, symptoms and response to oestrogen treatment in women approaching the menopause. Br Med J 979;1:983-985. 207. REDMOND GP. Androgenic Disorders. New York: LippincottRaven; 1995. 208. CHARMANDARI E, WEISE M, BORNSTEIN SR, EISENHOFER G, KEIL MF, CHROUSOS GP, MERKE DP. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab. 2002;87(5):2114-2120. 223. AVIS NE, STELLATO R, CRAWFORD S, JOHANNES C, LONGCOPE C. Is there an association between menopause status and sexual functioning? Menopause 2000;7:297-309. 224. HENDERSON VW. Estrogen, cognition, and a women's risk of Alzheimer's disease. Am J Med 1997;103(Suppl 3A):11-18. 209. ROSSOUW JE, ANDERSON GL, PRENTICE RL, LACR0OIX AZ, KOOPERBERG C, STEFANICK ML, JACKSON RD, BERESFORD SA, HOWARD BV, JOHNSON KC, KOTCHEN JM, OCKENE J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-333. 225. SHUGHRUE PJ, LANE MV, MERCHENTHALER I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 1997;388(4):507-525. 226. UTIAN WH. The true clinical features of postmenopause and oophorectomy, and their response to oestrogen therapy. S Afr Med J 1972;46:69-77. 210. WATTS NB, NOTELOVITZ M, TIMMONS MC, ADDISON WA, WIITA B, DOWNEY LJ. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995;85:529-537. 227. HOLTE A. Menopause, mood and hormone replacement therapy: methodological issues. Maturitas 1998;29:5-18. 228. COLLINS A, LANDGREN BM. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population based study. Maturitas 1994;20:101-111. 211. BATRINOS ML, PANITSA-FAFLIA C, KOUTSOUMANIS C, VOURLIOTI T, KOUTSILIERIS M. Surgical stress induces a marked and sustained increase of adrenal androgen secretion in postmenopausal women. In Vivo 1999;13(2):147-150. 229. DENNERSTEIN L, SMITH AMA, MORSE C. Psychological well being, mid-life and the menopause. Maturitas 1994;20:111. 212. POWELL LH, LOVALLO WR, MATTHEWS KA, MEYER P, MIDGLEY AR, BAUM A, STONE AA, UNDERWOOD L, MCCANN JJ, HERRO KJ, ORY MG. Physiologic Markers of Chronic Stress in Premenopausal, Middle-Aged Women. Psychosom Med 2002;64:502-509. 230. OLDENHAVE A, JASZMANN LJ, HASPELS AA, EVERAERD WT. Impact of climacteric on well being: A survey based on 5213 women 39 to 60 years old. Am J Obstet Gynecol 1993;168:772-780. 213. UTIAN WH. Definitive symptoms of postmenopause. Incorporating use of vaginal parabasal cell index. Estrogens in the postmenopause. Front Hormone Res 1975;3:74-93. 231. ERLIK Y, TATARYN IV, MELDRUM DR, LOMAX P, BAJOREK JG, JUDD HL. Association of waking episodes with menopausal hot flushes. JAMA 1981;245:1741-1744. 214. WILBUR JE, MILLER AM, MONTGOMERY A, CHANDLER P. Sociodemographic characteristics, biological factors and symptom reporting in midlife women. Menopause 1998;5:4351. 232. ZWEIFEL JE, O'BRIEN WH. A matter analysis of the effect of HRT upon depressed mood. Psycho Neurol Endocrinol 1997;22:189-212. 233. WIKLUND I, KARLBERG J, MATTSSON L. Quality of life of postmenopausal women on a regiment of transdermal estradiol therapy: A double blind placebo controlled study. AM J Obstet Gynecol 1993;168:824-830. 215. LAAN E, VAN LUNSEN RHW. Hormones and sexuality in postmenopausal women: A psychophysiological study. J Psychom Obstet Gynecol 1997;18:126-133. 234. SCHIFF I, REGESTEIN Q, TULCHINSKY D, RYAN KJ. Effect of estrogens on sleep and psychological state of hypogonadal women. JAMA 1979;242:2405-2414. 216. 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 Suppl 1:71-76. 235. HAYS J, OCKENE JK, BRUNNER RL, KOTCHEN JM, MANSON JE, PATTERSON RE, ARAGAKI AK, SHUMAKER SA, BRZYSKI RG, LACROIX AZ, GRANEK IA, VALANIS BG. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839-1854. 217. OVERLIE I, MOEN MH, HOLTE A, FINSET A. Androgens and estrogens in relation to hot flashes during the menopausal transition. Maturitas 2002;41:69-77. 218. HOLLANDER LE, FREEMAN EW, SAMMEL MD, BERLIN JA, GRISSO JA, BATTISTINI M. Sleep quality, estradiol levels, and behavioral factors in late reproductive age women. Obstet Gynecol 2001;98:391-397. 236. THE NORTH AMERICAN MENOPAUSE SOCIETY. Amended report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy. Menopause 2003;10:6-12. 237. CARDOZO L, BACHMANN G, MCCLISH D, FONDA D, BIRGERSON L. Meta analysis of estrogen therapy in the management of urogenital atrophy and postmenopausal women: Second report of the Horemones and Urogenital Therapy Committee. Obstet Gynecol 1998;92(4 Pt 2):722-727. 219. RANNEVIK G, CARLSTROM K, JEPPSSON S, BJERRE B, SVANBERG L. A prospective long-term study in women from menopause to postmenopause: Changing profiles of gonadotrophins, oestrogens and androgens. Maturitas 1986;8:297-307. 220. RANNEVIK G, JEPPSSON S, JOHNELL O, BJERRE B, LAURELL-BORULF Y, SVANBERG L. A longitudinal study of the perimenopausal transition: Altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 1995;21:103-113. 238. METTLER L, OLSEN PG. Long-term treatment of atrophic vaginitis with low-dose oestradiol vaginal tablets. Maturitas 1991;14:12-31. 239. MATTSSON LA, CULLBERG G, ERIKSSON O, KNUTSSON F. Vaginal administration of low-dose estradiol: effects on the endometrium and vaginal cytology. Maturitas 1989;11:217222. 221. SOWERS M, CRAWFORD SL, MORGENSTEIN D, STERNFELD B GOLD EB, GREENDALE, GA, EVANS D, NEER R, MATTHEWS K, Sherman. Design and methods of SWAN: a multicenter, multiethnic, community-based cohort study of mid- 240. CASPER F, PETRI E. Local treatment of urogenital atrophy 967 255. SMITH RN, HOLLAND EF, STUDD JWW. The symptomatology of progestin intolerance. Maturitas 1994;18:87-91. with an estradiol releasing vaginal ring: A comparative and a placebo controlled multi center study. Vaginal ring study group. IntUurogynecolJ Pelvic Floor Dysfunct 1999;10:171-176. 256. GREENDALE GA, REBOUSSIN BA, HOGAN P, BARNABEI VM, SHUMAKER S, JOHNSON S, BARRETT-CONNOR E. Symptom relief and side effects of postmenopausal hormones: results from the postmenopausal estrogen/progestin interventions trial. Obstet Gynecol 1998;92:982-988. 241. ERIKSEN B. A randomized, open, parallel group study on the preventive effect of an estradiol releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol 1999;180:1072-1079. 257. LOBITZ WC, LOBITZ GK. Resolving the sexual intimacy paradox: a developmental model for the treatment of sexual desire disorders. J Sex Marital Ther 1996;22:71-84. 242. WRITING GROUP FOR THE WOMEN'S HEALTH INITIATIVE INVESTIGATORS. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333. 258. PRIDAL CG, LOPICCOLO J. Multielement treatment of desire disorders: Integration of cognitive, behavioral, and systemic therapy. In: Leiblum SR and Rosen RC (eds). Principles and Practices of Sex Therapy, 3rd Ed. 2000. 243. SCARABIN PY, OGER E, PLU-BUREAU G. Differential association of oral and transdermal estrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-432. 259. SCHARFF DE. The sexual relationships: An object relations view of sex and the family. Florence, KY: Taylor Francis/Routledge; 1988. 244. MILLION WOMEN STUDY COLLABORATORS. Breast cancer and hormone replacement therapy in the million women study. Lancet 2003;362:419-427. 260. SCHNARCH DM. Constructing the sexual crucible: An integration of sexual and marital therapy. New York: Norton and Co.; 1991. 245. RAPP SR, ESPELAND MA, SHUMAKER SA, HENDERSON VW, BRUNNER RL, MANSEN JE, GASS ML, STEFANICK ML, LANE DS, HAYS J, JOHNSON KC, COKER LH, DAILEY M, BOWEN D, FOR THE WHIMS INVESTIGATORS. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:26632672. 261. TALMADGE LD, TALMADGE WC. Relationship sexuality: An understanding of low desire. J Sex Marital Ther 1986;12:321. 262. WAGNER G, FUGL-MEYER KS, FUGL-MEYER AR. Impact of erectile dysfunction on quality of life: patient and partner perspectives. Int J Impot Res 2000;12(Suppl 4):S144-S146. 246. SHUMAKER SA, LEGAULT C, RAPP SR, THAL L, WALLACE RB, OCKENE JK, HENDRIX SL, JONES BN III, ASSAF AR, JACKSON RD, KOTCHEN JM, WASSERTHEILSMOLLER S, WACTAWSKI-WENDE J, FOR THE WHIMS INVESTIGATORS. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651. 263. CAMPBELL WB, RIDLER BMF, MCGRATH C. Female sex function after aortic surgery. Cardiovasc Surg 1988;6:198-200. 264. STEWART DE, WONG F, DUFF S, MELANCON CH, CHEUNG AM. "What doesn't kill you makes you stronger": An ovarian cancer survivor survey. Gynecol Oncol 2001;83:537542. 265. HAVENGA K, MAAS CP, DERUITER MC, WELVAART K, TRIMBOS JB. Avoiding long-term disturbance to bladder and sexual function in pelvic surgery, particularly with rectal cancer. Semin Surg Oncol 2000;18:235-243. 266. POCARD M, ZINZINDOHOUE F, HAAB F, CAPLIN S, PARC R, TIRET E. A prospective study of sexual and urinary function before and after total mesorectal excision with autonomic nerve preservation for rectal cancer. Surgery 2002;131:368372. 267. BERGMARK K, AVALL-LUNDQVIST E, DICKMAN PW, HENNINGSOHN L, STEINECK G. Patient-rating of distressful symptoms after treatment for early cervical cancer. Acta Obstet Gynecol Scand 2002;81(5):443-450. 268. GRUMANN M, ROBERTSON R, HACKER NF, SOMMER G. Sexual functioning in patients following radical hysterectomy for stage 1B cancer of the cervix. Int J Gynecol Cancer 2001;11:372-380. 269. JENSEN PT, GROENVOLD M, KLEE MC, THRANOV I, MORTEN AP, MACHIN D. Early-stage cervical carcinoma, radical hysterectomy, and sexual function. Cancer 2004; 100: 97-106. 270. KRUMM S, LAMBERTI J. Changes in sexual behavior following radiation therapy for cervical cancer. J Psychosom Obstet Gynaecol 1995;14:51-63. 271. NUNNS D, WILLIAMSON K, SWANEY L, DAVY M. The morbidity of surgery and adjuvant radiotherapy in the management of endometrial carcinomas. Int J Gynecol Cancer 2000;10:233-238. 272. LEVIN RJ. The physiology of sexual arousal in the human female: a recreational and procreational synthesis. Arch Sex Behav 2002;31:405-411. 273. SHIFREN JL. Androgen deficiency in the oophorectomized women. Fertil Steril 2002;77(Suppl 4):S60-S62. 247. COL NF, HIROTA LK, ORR RK, ERBAN JK, WONG JB, LAU J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001;19:2357-2363. 248. O'MEARA ES, ROSSING MA, DALING JR, ELMORE JG, BARLOW WE, WEISS NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001;93:754-762. 249. EDEN JA, BUSH T, NAND S, WREN BG. A case-control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995;2:67-72. 250. HOLMBERG L, ANDERSON H, HABITS (hormonal replacement therapy after breastcancer - is it safe ?) a randomised comparison: trial stopped. Lancet 2004 ; 363: 453-455. 251. RIGGS BL, HARTMANN LC. Selective estrogen-receptor modulators - mechanisms of action and application of clinical practice. N Engl J Med 2003;348:618-629. 252. THE NORTH AMERICAN MENOPAUSE SOCIETY. Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society. Menopause 2003;10:113-132. 253. KLAIBER EL, BROVERMAN DM, VOGEL W, PETERSON LG, SNYDER MB. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology 1996;21:575-592. 254. HOLST J, BACKSTROM T, HAMMARBAK S, VON SCHOULTZ B. Progestogen addition during oestrogen replacement therapy: effects on vasomotor symptoms and mood. Maturitas 1989;11:13-20. 968 274. SAINI J, KUCZYNSKI E, GRETZ HF, SILLS EF. Supracervical hysterectomy versus total abdominal hysterectomy: perceived effects on sexual function. BMC Women's Health 2002;2:1. 293. HAMILTON GA, SEIDMAN RN. A comparison of the recovery period for women and men after an acute myocardial infarction. Heart Lung 1993;22:308-315. 275. BERMAN JR, ADHIKARI SP, GOLDSTEIN I. Anatomy and physiology of female sexual function and dysfunction: classification, evaluation and treatment options. Eur Urol 2000;38:2029. 294. WESTLAKE C, DRACUP K, WALDEN JA, FONAROW G. Sexuality of patients with advanced heart failure and their spouses or partners. J Heart Lung Transplant 1999;18:11331138. 276. BUTTLER-MANUEL SA, BUTTERY LDK, A'HERN RP, POLAK JM, Barton DPJ. Pelvic nerve plexus trauma at radical hysterectomy and simple hysterectomy. Cancer 2000;89::834841. 295. DENNERSTEIN L. Well being, symptoms and the menopausal transition. Maturitas 1996;23:147-57. 296. DENNERSTEIN L, LEHERT P, GUTHRIE J. The effects of the menopausal transition and biopsychosocial factors on well being. Arch Women Ment Health 2002;5:15-22. 277. GANZ PA, DESMOND KA, LEEDHAM B, ROWLAND JH, MEYEROWITZ BE, BELIN TR. Quality of life in long-term, disease-free survivors of breast cancer: A follow-up study. J Natl Cancer Inst 2002;94:39-49. 297. BENSLEY LS, VAN EENWYK JV, SIMMONS KW. Selfreported childhood sexual and physical abuse and adult HIVrisk behaviors and heavy drinking. Am J Prev Med 2000;18(2):151-158. 278. SCHOVER LR, YETMAN RJ, TUASON LJ, MEISLER E, ESSELSTYN CB, HERMANN RE, GRUNDFEST-BRONIATOWSKI S, DOWDEN RV. Partial mastectomy and breast reconstruction. A comparison of their effects on psychosocial adjustment, body image, and sexuality. Cancer 1995;75:54-64. 298. WYATT GE, LOEB TB, GANZ P, DESMOND KA. The prevalence and circumstances of child sexual abuse among breast cancer survivors: Relationship to high-risk sexual behaviors. In press. 279. GANZ PA, DESMOND KA, BELIN TR, MEYEROWITZ BE, ROWLAND JH. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol 1999;17:2371-2380. 299. WYATT GE, PETERS SD. Issues in the definition of child sexual abuse in prevalence research. Child Abuse Negl 1986a;10:231-240. 280. SPECTOR IP, LEIBLUM SR, CAREY MP, ROSEN RC. Diabetes and female sexual function: A critical review. Ann Behav Med 1993;15:257-264. 300. WYATT GE. The sexual abuse of Afro-American and White women in childhood. Child Abuse Negl 1985;9:507-519. 301. WYATT GE, LOEB TB, ROMERO G, SOLIS B, CARMONA JV. The prevalence and circumstances of child sexual abuse: Changes across a decade. Child Abuse Negl,1999;23:45-60. 281. SLOB AK, KOSTER J, RADDER JK, VAN DER WERFF TEN BOSCH JJ. Sexuality and psychophysiological functioning in women with diabetes mellitus. J Sex Marital Ther 1990;16:5969. 302. WYATT GE, PETERS SD. Methodological considerations in research on the prevalence of child sexual abuse. Child Abuse Negl 1986b;10:241-251. 282. ENZLIN P, MATHIEU C, VAN DEN BRUEL A, VANDERSCHUEREN D, DEMYTTENAERE K. Prevalence and predictors of sexual dysfunction in patients with type 1 diabetes. Diabetes Care 2003;26:409-414. 303. WYATT GE, NEWCOMB M, RIEDERLE M. Sexual abuse and consensual sex: Women's developmental patterns and outcomes. Newbury Park: Sage Publications; 1993. 283. MCCABE M. Relationship functioning and sexuality among people with multiple sclerosis. J Sex Res 2002;39:302-309. 304. GREEN AH. Overview of child sexual abuse. In: Kaplan SJ (ed). Family violence: A clinical and legal guide. Washington: American Psychiatric Press; 1996. pp. 73-104. 284. ZIVADINOV R, ZORZON M, BOSCO A, BRAGADIN LM, MORETTI R, BONFIGLI L, IONA LG, CAZZATO G. Sexual dysfunction in multiple sclerosis: II. Correlation analysis. Mult Scler 1999;5:428-431. 305. FINKELHOR D. Current information on the scope and nature of child sexual abuse. Sex Abuse Children, 1994;4(2):31-53. 285. KOCH T, KRALIK D, EASTWOOD S. Constructions of sexuality for women living with multiple sclerosis. J Adv Nurs 2002;39:137-145. 306. LOEB TB, WILLIAMS JK, CARMONA JV, RIVKIN I, WYATT GE, CHIN D, O'BRIEN A. Child Sexual Abuse and Sexual Functioning. Ann Rev Sex Res. In press. 286. WHIPPLE B, KOMISARUK BR. Sexuality and women with complete spinal cord injury. Spinal Cord 1997;35:136-138. 307. BROWNING C, LAUMANN EO. Sexual contact between children and adults: A life course perspective. Am Sociology Rev1997;62:540-560. 287. SIPSKI ML, ALEXANDER CJ, ROSEN R. Sexual arousal and orgasm in women: Effects of spinal cord injury. Ann Neurol 2001;49:35-44. 308. BRIERE J, RUNTZ M. Post sexual abuse trauma: Data and implications. J Interpers Violence 1987;2:367-379. 309. ROMERO GJ, WYATT GE, LOEB TB, VARGAS-CARMONA J, SOLIS B. The prevalence and circumstances of child sexual abuse among Latina women. Hispanic J Behav Sci; 1999;21(3):351-365. 288. HARRISON J, GLASS CA, OWENS RG, SONI BM. Factors associated with sexual functioning in women following spinal cord injury. Paraplegia 1995;33:687-692. 289. TEPPER MS, WHIPPLE B, RICHARDS E, KOMISARUK BR. Women with complete spinal cord injury: A phenomenological study of sexual experiences. J Sex Marital Ther 2001;27:615-623. 310. TRICKETT PK, PUTNAM FW. Impact of child sexual abuse on females: Toward a developmental, psychobiological integration. Am Psychol Soc 1993;4(2):81-87. 311. SROUFE LA, COOPER RG, DEHART GB. Physical and cognitive development in adolescence. Child development: Its nature and course. New York: McGraw Hill, 1992. 290. ODDY M. Sexual relationship following brain injury. Sex Rel Ther 2001;16:247-259. 291. GIAQUINTO S, BUZZELLI S, DI FRANCESCO L, NOLFE G. Evaluation of sexual changes after stroke. J Clin Psychiatry 2003;64(3):302-307. 312. TYLER KA, WHITBECK LB, HOYT, DR., YODER KA. Predictors of self-reported sexually transmitted diseases among homeless and runaway adolescents. J Sex Res 2000;37:369-377. 292. MULLER JE, MITTLEMAN MA, MACLURE M, SHERWOOD JB, TOFLER GH. Triggering myocardial infarction by sexual activity: Low absolute risk and prevention by regular physical exertion. JAMA 1996;275;1405-1409. 313. POLUSNY M.A, FOLLETTE VM. Long-term correlates of child sexual abuse: Theory and review of the empirical literature. Appl Prev Psychol 1995;4:143-166. 969 334. THOMAS TG, MUNDE PF. A practical treatise on the diseases of women. Philadelphia: Lea Brothers and Co.; 1891. 314. ELLIOTT DM, BRIERE J. Sexual abuse trauma among professional women: Validating the Trauma Symptom Checklist-40 (TSC-40). Child Abuse Negl 1992;16:391-398. 335. DE POZZI SJ. Traité de gynécologie clinique et opératoire. Paris, 1890; 2nd Ed., 1891; 4th Ed. pp.1905-1907. Translated into German, English, and Russian. This treatise won him the title of Laureate of the Institute. 315. WEST CM, WILLIAMS LM, SIEGEL JA. Adult sexual re-victimization among black women sexually abused in childhood: A prospective examination of serious consequences of abuse. Child Maltreat 2000;1:49-57. 336. MCKAY M. Dysesthetic ("essential") vulvodynia. J Reprod Med 1984;29:457. 316. WYATT GE, MYERS HF, WILLIAMS JK, KITCHEN CR, LOEB T, CARMONA JV, WYATT LE, CHIN D, PRESLEY N. Does a history of trauma contribute to HIV risk for women of color? Implications for prevention and policy. Am J Public Health 2002;92(4):1-7. 337. MCKAY M. Vulvodynia. A multifactorial clinical problem. Arch Dermatol 1989;125(2):256-262. Review 338. REISSING ED, BINIK YM, KHALIFÉ S. Does vaginismus exist? A critical review of the literature. J Nerv Mental Dis 1999;187(5):261-274. 317. BECKER JV, SKINNER LJ, ABEL GG, TREACY EC. Incidence and types of sexual dysfunctions in rape and incest victims. J Sex Marital Ther 1982;8:65-74. 339. MEANA M., BINIK YM, KHALIFÉ S, COHEN D. Dyspareunia. sexual dysfunction or pain syndrome? J Nerv Mental Dis 1997;185(9):561-569. 318. DAVIS JL, PETRETIC-JACKSON PA, TING L. Intimacy dysfunction and trauma symptomatology: Long-term correlates of different types of child abuse. J Trauma Stress 2001;14:63-79. 340. VAN LANKVELD JJ, BREWAEYS AM, TER KUILE MM, WEIJENBORG PTHM. Difficulties in the differential diagnosis of vaginismus, dyspareunia and mixed sexual pain disorder. J Psychosom Obstet Gynaecol 1995;16(4):201-209. 319. BERMAN LA, BERMAN JR, BRUCK D, PAWAR RV, GOLDSTEIN I. Pharmacotherapy or psychotherapy?: Effective treatment for FSD related to unresolved childhood sexual abuse. J Sex Marital Ther 2001;27(5):421-425. 341. KRUIFF DE MD, TER KUILE MM, WEIJENBORG PTHM, VAN LANKVELD JJDM: Vaginismus and dyspareunia: is there a difference in clinical presentation? J Psychosom Obstet Gynaecol 2000;21:149-155. 320. LODICO MA, DICLEMENTE RJ. The association between childhood sexual abuse and prevalence of HIV-elated risk behaviors. Clin Pediatrics 1994;33(8):498-502. 342. BASSON R. Lifelong vaginismus: A clinical study of 60 consecutive cases. J Soc Gynecol Obstet Can 1996;3:551-561. 321. ABU-SAHLIEH SA. To mutilate in the name of Jehovah or Allah: Legitimization of male and female Circumcision. Med Law 1994;13(7-8):575-622. 343. WESSELMANN U, BURNETT AL, HEINBERG LJ. The urogenital and rectal pain syndromes. Pain 1997;73:269-294. 322. BRIGHOUSE R. Ritual female circumcision and its effects on female sexual function. Can J Human Sexuality 1992;1:3-10. 344. BURNETT AL, WESSELMANN U. History of the neurobiology of the pelvis. Urology 1999;53:1082-1089. 323. ELDERFRAWI, LOFTY MH, DANDASH KF, REFAAT AH, EYADA M. Female genital mutilation and its psychosexual impact. J Sex Marital Ther 2001;27:465-473. 324. MCDONALD CF. Circumcision of the female. Gen Practitioner 1958;18(3):98-99. 325. TOUBIA N. Caring for women with circumcision: A technical manual for health care providers. Brit Med J 2000;320:1481. 326. WYATT GE. Stolen Women: Reclaiming our sexuality, taking back our lives. New York: John Wiley & Sons, Inc.; 1998. pp. 79. 327. WALKER A, PARMAR P. Warrior marks: Female genital mutilation and the sexual blinding of women. New York: Harcourt Brace Jovanovich; 1993. 328. WHITEHORN A, OYEDEJI A, MAINGAY S. female genital mutilation: cultural and psychological implications. from Sex Rel Ther 2002;17(2):161-70. 329. MICHELSON D, BANCROFT J, TARGUM SD. Female sexual dysfunction associated with antidepressant administration: A randomized placebo controlled study of pharmacological intervention. Am J Psychiatry 2000;157:239-243. 330. KENNEDY S, EISFELD BS, DICKENS SE, BACCHIOCHI JR, BAGBY M. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline and venlafaxine. J Clin Psychiatry 2000;61:276-281. 331. MICHELSON D, KOCIBAN K, TAMURA R, MORRISON MF. Mirtazapine, yohimbine or olansapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction: A randomized, placebo-controlled trial. J Psychiatric Res 2002;36:147-152. 332. MASAND PS, ASHTON A, GUPTA S, FRANK B. Sustained release bupropion SR for SSRI-induced sexual dysfunction: a randomized, double-blind placebo-controlled parallel group study. Am J Psychiatry 2001; 158:805-807. 345. SHAFIK A, DOSS S. Surgical anatomy of the somatic terminal innervation to the anal and urethral sphincters: role in anal and urethral surgery. J Urol;1999;161:85-89. 346. BORS E, COMARR AE. Neuro-anatomy and neuro-physiology. In: Neurological urology. New York: Karger; 1971. pp. 61128. 347. MORRISON JFB. Role of higher levels of the central nervous system. In: Torrens M, Morrison JFB (eds). The physiology of the lower primary tract. London: Springer-Verlag; 1987. pp. 237-274. 348. DE GROAT WC, BOOTH AM, YOSHIMURA N. Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi CA (ed). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993. pp. 227-290. 349. DE GROAT WC Neurophysiology of the pelvic organs. In: Rushton DN (ed). Handbook of neuro urology. New York: Marcel Dekker Inc; 1994. pp. 55-93. 350. APKARIAN AV, BRÜGGEMAN J, SHI T, AIRAPETIAN LR. A thalamic model for true and referred visceral pain. In: G. F. Gebhart (ed.). Visceral pain, progress in pain research and management. Seattle: IASP Press; 1994. pp. 217-259. 351. BERKLEY KJ, HUBSCHER CH. Visceral and somatic sensory tracks through the neuraxis and their relation to pain: lessons from the rat female reproductive system. In: Gebhart GF (ed). Visceral pain, progress in pain research and management. Seattle: IASP Press; 1994. pp. 195-216. 352. CECHETTO D. A thalamic model for true and referred visceral pain. In: G. F. Gebhart (ed.). Visceral pain, progress in pain research and management, Vol 5, Seattle: IASP Press; 1994. pp. 261-290. 353. DAIL WG. Autonomic innervation of male reproductive genitalia. In: Maggi CA (ed). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993. pp. 69-101. 333. DICKINSON RL. Human sex anatomy, a topographical hand atlas, 2nd Ed. London: Baillière, Tindall & Cox; 1949. p. 102. 970 374. KOMISARUK B, BIANCA R, SANSONE G, GOMEZ LE, CUEVA-RULON R, BEYER C, WHIPPLE B. Brain-mediated responses to vagino-cervical stimulation in spinal cord-transected rats: role of the vagus nerves. Brain Res 1996;708:128-134. 354. BALJET B, DRUKKER J. The extrinsic innervation of the pelvic organs in the female rat. Acta Anat 1980;107:241-267. 355. WALSH PC, DONKER PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492-497. 375. BERKLEY KJ, HUBSCHER CH, WALL PD. Neuronal responses to stimulation of the cervix, uterus, colon, and skin in the rat spinal cord. J Neurophysiol 1993;69:545-556. 356. LUE TF, ZEINEH SJ. SCHMIDT RA, TANAGHO EA. Neuroanatomy of penile erection: its relevance to iatrogenic impotence. J Urol 1984;131:273-280. 376. BERKLEY KJ, HUBSCHER CH: Visceral and somatic sensory tracks through the neuraxis and their relation to pain: Lessons from the rat female reproductive system. In: G. F. Gebhart (ed.). Visceral Pain. Seattle, WA: IASP Press; 1995a. pp. 195-216. 357. LEPOR H, GREGERMAN M, CROSBY R, MOSTOFI FK, WALSH PC. Precise localization of the autonomic nerves from the pelvic plexus to the corpora cavernosa: a detailed anatomical study of the adult male pelvis. J Uro1;985;133:207-212. 358. BURNSTOCK G. Innervation of bladder and bowel. In: G. Bock, J. Whelan (eds). Neurobiology of incontinence. Wiley, Chichester: Ciba Foundation Symposium, 1990. pp. 2-26. 377. BERKLEY KL, BENOIST JM, GAUTRON M, GUILBAUD G. Responses of neurons in the caudal intralaminar thalamic complex of the rat to stimulation of the uterus, vagina, cervix, colon and skin. Brain Res 1995b;695:92-95. 359. JÄNIG W, MCLACHLAN EM. Organization of lumbar spinal outflow to distal colon and pelvic organs. Physiol Rev 1987;67:1332-1404. 378. BRADSHAW HB, BERKLEY KB. Estrous changes in responses of rat gracile nucleus neurons to stimulation of skin and pelvic viscera. J Neurosci 2000;20:7722-7727. 360. MCKENNA KD, NADELHAFT I. The organization of the pudendal nerve in the male and female cat. J Comp Neurol 1986;248:532-549. 379. BERKLEY KJ, WOOD E, SCOFIELD SL, LITTLE M. Behavioral responses to uterine or vaginal distension in the rat. Pain 1995c;61:121-131. 361. HANCOCK MB, PEVETO CA. Preganglionic neurons in the sacral spinal cord of the rat: an HRP study. Neurosci Letter 1979:11:1-5. 362. NADELHAFT I, BOOTH AM. The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: a horseradish peroxidase study. J Comp Neurol 1984;226:238-245. 363. HILLIGES M, FALCONER C, EKMAN-ORDEBERG G, JOHANSSON O. Innervation of the human vaginal mucosa as revealed by PGP 9.5 immunohistochemistry. Acta Anat 1995;153:119-126. 364. LINCOLN J, BURNSTOCK G. Autonomic innervation of the urinary bladder and urethra. In: Maggi CA, (ed). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993. pp. 33-68. 365. ELBADAWI A. Functional anatomy of the organs of micturition. Urol Clin North Am 1996;23:177-210. 366. BARBER MD, BREMER RE, THOR KB, DOLBER PC, KUEHL TJ, COATES KW. Innervation of the female levator ani muscles. Am J Obstet Gynecol 2002;187:64-71. 367. DIETEMANN JL, SICK H, WOLFRAM-GABEL R, CRUZ DA SILVA R, KORITKE JG, WACKENHEIM A. Anatomy and computed tomography of the normal lumbosacral plexus. Neuroradiology 1987;29:58-68. 368. JUENEMANN KP, LUE TF, SCHMIDT RA, TANAGHO EA. Clinical significance of sacral and pudendal nerve anatomy. J Urol 1988;139:74-80. 380. KOMISARUK BR, LARSSON K. Suppression of a spinal and a cranial nerve reflex by vaginal or rectal probing in rats. Brain Res 1971;35:231-235. 381. KOMISARUK BR, WHIPPLE B. The suppression of pain by genital stimulation in females. Annu Rev Sex Res 1995;6:151185. 382. FRIEDRICH EG. The vulvar vestibule. J Reprod Med 1983;28:773-777. 383. MARINOFF SC, TURNER ML. Vulvar vestibulitis syndrome. Dermatol Clin 1992;10(2):435-444. 384. WESTROM LV, WILLEN R Vestibular nerve fiber proliferation in vulvar vestibulitis syndrome. Obstet Gynecol 1998;91:572576. 385. WOODRUFF JD, FRIEDRICH ED. The vestibule. Clin Obstet Gynecol 1985;28:134-141. 386. KRANTZ KE. Innervation of the human vulva and vagina. Obstet Gynecol 1958;12:382-396. 387. IGGO A, ANDRES KH. Morphology of cutaneous receptors. Annu Rev Neurosci 1982;5:1-31. 388. BOHM-STARKE N, HILLIGES M, FALCONER C, RYLANDER E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1998;46:256-260. 389. DE GROAT WC, BOOTH, AM. Synaptic transmission in pelvic ganglia. In: Maggi CA (ed). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993a. pp. 91-347. 390. PAPKA RE TRAURIG HH. Autonomic efferent and visceral sensory innervation of the female reproductive system: special reference to neurochemical markers in nerves and ganglionic connections. In: Maggi CA (ed.). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993. pp. 423-466. 391. VLASKOVSKA M, KASAKOV L, RONG W, BODIN P, BARDINI M, COCKAYNE DA, FORD APDW, BURNSTOCK G. P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 2001;21:5670-5677. 369. MATZEL KE, SCHMIDT RA, TANAGHO EA. Neuroanatomy of the striated muscular anal continence mechanism: implications for the use of neurostimulation. Dis Colon Rectum 1990;33:666-673. 370. WALL LL. The muscles of the pelvic floor. Clin Obstet Gynecol 1993;36:910-925. 371. RETZKY SS, ROGERS RM, RICHARDSON AC. Anatomy of female pelvic support. In: Brubaker LTT, Saclarides T (ed). The female pelvic floor: disorders of function and support. Philadelphia: F.A. Davis; 1996. pp. 3-21. 392. DE GROAT WC, BOOTH AM. Neural control of penile erection. In: Maggi CA (ed.). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993b. pp. 467-524. 372. DELANCEY JOL. Surgical anatomy of the female pelvis. In: Rock JA, Thompson JD (eds). TeLinde's operative gynecology, 8th Ed. Philadelphia: PA, Lippincott-Raven; 1997. pp. 63-94. 373. BURNETT AL, SAITO S, MAGUIRE MP, YAMAGUCHI H, CHANG TK, HANLEY DF. Localization of nitric oxide synthase in spinal nuclei innervating pelvic ganglia. J Urol 1995b;153:212-217. 393. LEVIN RJ. VIP, vagina, clitoral and periurethral glans - an update on human female genital arousal. Exp Clin Endocrinol 1991;98:61-69. 971 394. WAGNER G. Aspects of genital physiology and pathology. Sem Neurol 1992;12:87-97. (eds). Behandelingsstrategieën bij seksuele disfuncties. Houten: Bohn Stafleu Van Loghum; 2001. 395. JÄNIG W, KOLTZENBURG M. PAIN ARISING FROM THE UROGENITAL tract. In: Maggi CA (ed). Nervous control of the urogenital system. Chur, Switzerland: Harwood Academic Publishers; 1993. pp. 525-578. 415. CARTER J, FOWLER L, CARLSON J, TWIGGS LB. How accurate is the pelvic examination as compared to transvaginal sonography? A prospective, comparative study. J Reprod Med 1994:39:32-34. 396. BAYLISS WM. On the origin from the spinal cord of vasodilator fibers of the hind limb and on the nature of these fibers. J Physiol 1901;26:173-209. 416. BASSON R. Sexuality and sexual disorders. Clin Updates Women's Health Care 2003;11(2):1-94. 417. FRIEDRICH EG JR: Vulvar Vestibulitis Syndrome. J Reprod Med 1987;32:110-115. 397. LIN Q, WU J, WILLIS WD. Dorsal root reflexes and cutaneous neurogenic inflammation after intradermal injection of capsaicin in rats. J Neurophysiol 1999;82:2602-2626. 418. PUKALL CF, PAYNE KA, BINIK YM, KHALIFÉ S. Pain measurement in vulvodynia. J Sex Marital Ther 2003;29(s):111-120. 398. MAYER EA, RAYBOULD H, KOELBEL C. Neuropeptides, inflammation, and motility. Dig Dis Sci 1988;33(Suppl):S71S77. 419. DANIELSSON I, SJÖBERG I, WIKMAN M. Vulvar vestibulitis. Medical psychosexual and psychosocial aspects, a casecontrol study. Acta Obstet Gynecol 2000;79(10):872-878. 399. PINTER E, SZOLCANYI J. Plasma extravasation in the skin and pelvic organs evoked by antidromic stimulation of the lumbosacral dorsal roots in the rat. Neuroscience 1995;68:603-614. 420. GATES EA, GALASK RP. Psychological and sexual functioning in women with vulvar vestibulitis. Journal of Psychosomatic Obstet Gynecol 2001;22:221-228. 400. WESSELMANN U, LAI J. Mechanisms of referred visceral pain. Uterine inflammation in the adult virgin rat results in neurogenic plasma extravasation in the skin. Pain 1997;73:309-317. 421. JANTOS M, WHITE G. The vestibulitis syndrome: Medical and psychosexual assessment of a cohort of patients. J Reprod Med 1997;42(3):145-152. 401. GEPPETTI P. Neurogenic inflammation. Munchen: K.G. Saur Verlag; 1996. 422. DANIELSSON I, EISEMANN M, SJÖBERG I, WIKMAN M. Vulvar vestibulitis: A multi-factorial condition. BJOG 2001;108:456-461. 402. ELBADAWI A. Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis. Urology 1997;49(Suppl):14-40. 423. DUDDLE M. Etiological factors in the unconsummated marriage. J Psychosom Res 1977;21:157-160. 403. STEERS WD, TUTTLE JB: Neurogenic inflammation and nerve growth factor: possible roles in interstitial cystitis. In: GR Sant. Interstitial cystitis. Philadelphia: Lippincott-Raven Publishers; 1997. pp. 67-75. 424. GRANOT M, FRIEDMAN M, YARNITSKY D, ZIMMER EZ. Enhancement of the perception of systemic pain in women with vulvar vestibulitis. BJOG 2002;109:863-866. 425. KENNEDY P, DOHERTY N, BARNES J. Primary vaginismus: a psychometric study of both partners. Sex Marital Ther 1995;10:9-22. 404. PROCACCI P, MARCESCA M. Referred pain from somatic and visceral structures. Cur Rev Pain 1999;3:96-99. 405. PROCACCI P, ZOPPI M, MARCESCA M. Heart, vascular and homeopathic pain. In: P. D. Wall, R. Melzack : Textbook of pain, 4th Ed. New York. Churchill Livingstone; 1999. pp. 621-639. 426. MEANA M, BINIK YM, KHALIFÉ S, COHEN DR. Biopsychosocial profile of women with dyspareunia. Obstet Gynecol 1997;90(4):583-589. 406. BOHM-STARKE N, HILLIGES M, BRODDA-JANSEN G, RYLANDER E, TOREBJRK E. Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis. Pain 2001;94:177-183. 427. NUNNS D, MANDAL D. Psychological and psychosexual aspects of vulvar vestibulitis. Genitour Med 1997;73:541-544. 428. PAYNE KA, BINIK YM, AMSEL R, KHALIFÉ S, LAHAIE MA. An investigation of fear-mediated hypervigilence in women suffering from vulvar vestibulitis syndrome. Paper presented at the Annual Meeting of the Society for the Scientific Study of Sexuality, Montreal, Canada; 2002. 407. PUKALL CF, BINIK YM, KHALIFÉ S, AMSEL R, ABBOTT FV. Vestibular tactile and pain thresholds in women with vulvar vestibulitis syndrome. Pain 2002;96:163-175. 408. SONNI L, CATTANEO A, DE MARCO A, DE MAGNIS C, CARLI P, MARABINI S. Idiopathic vulvodynia clinical evaluation of the pain threshold with acetic acid solutions. J Reprod Med 1995;40:337-341. 429. REISSING ED, BINIK YM, KHALIFÉ S, COHEN D, AMSEL R. Etiological correlates of vaginismus: Sexual and physical abuse, sexual knowledge, sexual self-schema, and relationship adjustment. J Sex Marital Ther 2003;29:47-59. 409. DEVOR M, SELTZER Z. Pathophysiology of damaged nerves in relation to chronic pain. In: PD Wall, R Melzack (eds). Textbook of pain, 4th Ed. New York: Churchill Livingstone; 1999, pp. 129-164. 430. SCHMIDT S, BAUER A, GREIF C, MERKER A, ELSNER P, STRAUSS B. Vulvar pain: Psychological profiles and treatment responses. J Reprod Med 2001;46(4),377-384. 431. SCHOVER LR, YOUNGS DD, CANNATA R. Psychosexual aspects of the evaluation and management of vulvar vestibulitis. Am J Obstet Gynecol 1992;167(3),630-636. 410. MCKAY M. Dysesthetic (essential) vulvodynia. Treatment with amytriptilyne J Reprod Med 1993;37:9-13. 411. FRENKEN J, VAN TOL P. Seksuele problemen in de gynaecologische praktijk. Med Contact 1987;42:150-154. 432. VAN LANKVELD JJ, WEIJENBORG PT, TER KUILE MM. Psychologic profiles of and sexual function in women with vulvar vestibulitis and their partners. Obstet Gynecol 1996;88(1):65-70. 412. BACHMANN GA, LEIBLUM SR, GRILL J. Brief sexual inquiry in gynecologic practice. Obstet Gynecol 1989;73:425427. 433. MEANA M, BINIK I, KHALIFÉ S, COHEN D. Affect and marital adjustment in women's rating of dyspareunic pain. Can J Psych 1998;43(4):381-385. 413. WIJMA B, SCHEI B, SWAHNBERG K, HILDEN M, OFFERDAL K, PIKARINEN U, SIDENIUS K, STEINGRIMSDOTTIS T, STOUM H, HALMESMÄKI E. Emotional, physical, and sexual abuse in patients visiting gynecology clinics: a Nordic cross-sectional study. Lancet 2003;361:2107-2113. 434. MEANA M, BINIK I, KHALIFÉ S, COHEN D. Psychosocial correlates of pain attributions in women with dyspareunia. Psychosom 1999;40:497-502. 414. TER KUILE MM, WEIJENBORGH PHTM. Oppervlakkige dyspareunie bij de vrouw. In: Hengeveld MW, Brewaeys A 435. VAN DER VELDE J, EVERAERD W. Voluntary control over 972 pelvic floor muscles in women with and without vaginistic reactions. Int Urogynecol J 1999;10:230-236. 454. MAURICE WL. Intercourse difficulties in women: Pain, discomfort and fear. In: Sexual medicine in primary care. Toronto: Mosby; 1999. pp. 277-297. 436. VAN DER VELDE J, EVERAERD W. The relationship between involuntary pelvic floor muscle activity, muscle awareness and experienced threat in women with and without vaginismus. Behav Res Ther 2001a:39:395-408. 455. VAN DE WIEL HBM, JASPERS JPM, WEIJMAR SCHULTZ WCM, GAL J. Treatment of vaginismus; A review of concepts and treatment modalities. J Psychosom Obstet Gynecol 1990;11:1-18. 437. VAN DER VELDE J, EVERAERD W. Vaginismus, a component of a general defensive reaction. An investigation of pelvic floor muscle activity during exposure to emotion-inducing film excerpts in women with and without vaginismus. Int Urogynecol J 2001b;12:328-331. 456. O'DONOHUE W, DOPKE C A, SWINGEN DN. Psychotherapy for female sexual dysfunction: A review. Clin Psych Rev 1997;17(5):537-566. 457. KLEINPLATZ PJ. Sex therapy for vaginismus. A review, critique and humanistic alternative. J Humanistic Psych 1998;38(2):51-81. 438. BERGERON S, BROWN C, LORD MJ, OALA M, BINIK YM, KHALIFÉ S. Physical therapy for vulvar vestibulitis syndrome: a retrospective study. J Sex Marital Ther 2002;28:183-192. 458. DRENTH JJ. Vaginismus and the desire for a child. J Psychosom Obstet Gynecol. 1988;9:125-137 439. HAWTON K, CATALAN J. Sex therapy for vaginismus: characteristics of couples and treatment outcome. Sex Marital Ther 1990;5:39-48. 459. FRIEDMAN U. Virgin wives: A study of unconsummated marriages. London: Tavistock Publications; 1957. 440. SCHNYDER U, SCHNYDER-LÜTHI C, BALLINARI P, BLASER A. Therapy for vaginismus: In vivo versus in vitro desensitization. Can J Psych 1998;43:941-944. 460. GLAZER HI, JANTOS M, & HARTMANN EH. Dysthetic Vulvodynia: Long-term follow-up after treatment with surface electromyography-assisted pelvic floor muscle rehabilitation. J Reprod Med 2000;45:798-802. 441. SCHOLL GM. Prognostic variables in treating vaginismus. Obstet Gynecol 1988;72:231-235. 442. SCHOVER LR, YOUNGS DD, CANNATA R. Psychosexual aspects of the evaluation and management of vulvar vestibulitis. Am J Obstet and Gynecol 1992;167(3):630-636. 461. GLAZER HI, JANTOS M, HARTMANN EH, SWENCIONIS C. Electromyographic comparisons of the pelvic floor in women with dysesthetic vulvodynia and asymptomatic women. J Reprod Med 1998;43:959-962. 443. BROTTO LA, BASSON R, GEHRING D. Psychological profiles among women with vulvar vestibulitis syndrome: a chart review. J Psychosom Obstet Gynecol 2003;24(3): In press. 462. WHITE G, JANTOS M, GLAZER H. Establishing the diagnosis of vulvar vestibulitis. J Reprod Med 1997;42:157-160. 463. BERGERON S, BINIK YM, KHALIFÉ S, PAGIDAS K, GLAZER HI. A randomized comparison of group cognitive-behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Pain 2001;91:297-306. 444. WEIJMAR SCHULTZ WCM, GIANOTTEN WL, VAN DER MEIJDEN WI, VAN DE WIEL HBM, BLINDEMAN B, CHADA S, DROGENDIJK AC. Behavioural approach with or without surgical intervention for the vulvar vestibulitis syndrome: A prospective randomized and non-randomized study. J Psychosom Obstet Gynecol 1996;17:143-148. 464. BRUBAKER LTT. Saclarides TJ (ed). The female pelvic floor: Disorders of function and support. Philadelphia: F.A. Davis Company; 1996. 445. BERGERON S, BINIK YM, KHALIFÉ S, PAGIDAS K, GLAZER HI, MEANA M, AMSEL R. A randomized comparison of group cognitive-behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Pain 2001;91:297-306. 465. DEVROEGE G. Front and rear: The pelvic floor is an integrated functional structure. Med. Hypotheses 1999;52(2):147-153. 466. HOLSTEGE G. The emotional motor system in relation to the supraspinal control of micturition and mating behavior. Behav Brain Res 1998;92:103-109. 446. GLAZER HI, RODKE G, SWENCIONIS C, HERTZ R, YOUNG AW. The treatment of vulvar vestibulitis syndrome by electromyographic biofeedback of pelvic floor musculature. J Reprod. Med 1995;40:283-290. 467. BLOK BFM, STURMS LM, HOLSTEGE G. A PET study on cortical and subcortical control of pelvic floor muscles. J Comp Neurol 1997;389:535-544. 447. BERGERON S, BINIK YM, KHALIFÉ S, PAGIDAS K, GLAZER HI. A randomized comparison of group cognitive-behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Pain 2001;91:297-306. 468. BLOK BFM, STURMS LM, HOLSTEGE G. Brain activation during micturition in women. Brain 1998;121:2033-2042. 469. FOSTER DC. Vulvar disease. Obstet Gynecol 2002;100:145163. 448. MENSE S, SIMONS DJ, RUSSELL IJ. Muscle pain: Understanding its nature, diagnosis and treatment. Philadelphia: Lippincott Williams & Wilkins; 2001. 470. SILVO S, AHONEN R, MIKANDER H, HEMMINKI E. Selfmedication with vaginal anti-fungal drugs: Physicians' experiences and women's utilization patterns. Fam Practice 2000;17:145-149. 449. OF SALERNO T: The diseases of women (E. Mason-Hohl trans). Los Angeles: The Ward Ritchie Press, 1547/1940:140. 471. FERRIS DG, NYIRJESY P, SOBEL JD, SOPER D, PAVLETIC A, LITABER M. Over-the-counter antifungal drug misuse associated with patient-diagnosed vulvo-vaginal candidiasis. Obstet Gynecol 2002;99:419-425. 450. SIMS MJ. On vaginismus. Transcripts Obstetrical Society London. 1861;3:356-367. 451. ABRAMOV L, WOLMAN J, HIGGINS MP. Vaginismus: An important factor in the evaluation and management of vulvar vestibulitis syndrome. Gynecol Obstet Invest 1994;38(3):194197. 472. MARIN MG, KING R, SFAMENI S, DENNERSTEIN GJ. Adverse behavioral and sexual factors in chronic vulvar disease. Am J Obstet Gynecol 2000.183:34-38. 473. MCKAY M Subsets of vulvodynia. J Reprod Med 1988;33:695698. 452. REISSING ED, BINIK YM, KHALIFÉ S, COHEN D, AMSEL R. Vaginal spasm, pain and behavior: An empirical investigation of the diagnosis of vaginismus. Arch. Sex Behav. In press. 474. HANSEN A, CARR K, JENSEN JT. Characteristics and initial diagnoses in women presenting to a referral center for vulvovaginal disorders in 1996-2000. J Reprod Med 2002;47:854-860. 453. JOHNSON EW. The myth of skeletal muscle spasm. Am J Phys Med Rehabil 1989;68:1-2. 973 496. SARMA AV, FOXMAN B, BAYIRLI B, HAEFNER H, SOBEL JD. Epidemiology of vulvar vestibulitis syndrome: an exploratory case-control study. Sex Transm Infect 1999;75:320-326. 475. VIRGILI A, BACILIERI S, CORAZZA M. Managing vulvar lichen simplex chronicus. J Reprod Med 2001;46:343-346. 476. BORNSTEIN J, HEIFETZ S, KELLNER Y, STOLAR Z, ABRAMOVICI H. Clobetasol dipropionate 0.05% versus testosterone propionate 2% topical application for sever vulvar lichen sclerosis. Am J Obstet Gynecol 1998;178:80-84. 497. MANN MS, KAUFMAN RH, BROWN JR D, ADAM E. Vulvar vestibulitis: significant clinical variables and treatment outcome. Obstet Gynecol 1992;79:122-125. 498. WITKIN SE, GERBER S, LEDGER WJ. Differential characterization of women with vulvar vestibular syndrome. Am J Obstet Gynecol 2002;287:589-594. 477. LEWIS FM. Vulval lichen planus (review). Br J Dermatol 1998;138:569-575. 478. PAAVONEN J. Vulvodynia-a complex syndrome of vulvar pain. Acta Obstet Gynecol Scand 1995;74:243. 499. NYIRJESY P. Vulvar vestibulitis syndrome: a post-infectious entity? Curr Infect Dis Rep 2000;2:531-535. 479. DENBOW ML, BYRNE MA. Prevalence, causes and outcome of vulvar pain in a genito-urinary medicine clinic setting. Int J STD AIDS 1998;9:88-91. 500. MEYER RA, DAVIS KD, COHEN RH. Mechanically insensitive afferents (MIAs) in cutaneous nerves of the monkey. Brain Res 1991;561:252. 480. HARLOW BL, WISE LA, STEWART EG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol 2001;185:545-550. 501. LEVINE J, TAIWO Y. Inflammatory pain. Textbook of Pain, 3rd Ed. Edinburgh: Churchill Livingstone; 1994. p. 45. 502. BOHM-STARKE N, HILLIGES M, FALCONER C, RYLANDER E. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1999;48:270. 481. GOETSCH MF. Vulvar vestibulitis: prevalence and historic features in a general gynecologic practice population. Am J Obstet Gynecol 1991;164:1609-1614. 482. BAGGISH MS, MIKLOS JR. Vulvar pain syndrome: A review. Obstet Gynecol Surv 1995;50:618-627. 503. BOHM-STARKE N, HILLIGES M, BLOMGREN B, FALCONER C. Increased blood flow and erythema in the posterior vestibular mucosa in vulvar vestibulitis. Obstet Gynecol 2001;98:1067-1074. 483. NUNNS D, HIGINS SP, MANDAL D. National vulvodynia questionnaire. Int J STD AIDS 1995;6(5):366-367. 484. HARLOW BL, STEWART EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Wom Assoc 2003;58:8288. 504. HAYNES RB, TAYLOR DW, SACKETT DL. Compliance in Health Care. Baltimore: John Hopkins University Press; 1979. 505. BORNSTEIN J, ZARFATI D, GOLDIK Z, GODIK H, ABRAMOVICI H: Vulvar vestibulitis: physical or psychosexual problem? Obstet Gynecol 1999;93:5 pt:876-880. 485. PYKA RE, WILKINSON EJ, FRIEDRICH EG, CROKER BP. The histopathology of vulvar vestibulitis syndrome. Int J Gynecol Pathol 1988;249-257. 506. NYIRJESY P, SOBEL JD, WEITZ MV, LEAMAN DJ, SMALL MJ, GELONE SP. Sex Transm Infect 2001;77:53-57. 486. CHADHA S, GIANOTTEN WL, DROGENDIJK AC, WEIJMAR SCHULTZ W, BLINDEMAN LA, VAN DER MEIJDEN WI: Histopathologic features of vulvar vestibulitis. Int J Gynecol Pathol 1998;17:7-11. 507. HAEFNER HK. Critique of new gynecologic surgical procedures: Surgery for vulvar vestibulitis. Clin Obstet Gynecol 2000;45(3):689-700. 508. BERGERON S, BOUCHARD C, FORTIER M, BINIK Y, KHALIFÉ S. The surgical treatment of vulvar vestibulitis syndrome a follow-up study. J Sex Marital Ther 1997;23(4):317325. 487. FOSTER DC, HASDAY JD. Elevated tissue levels of interleukin -1ß and tumor necrosis factor-a in vulvar vestibulitis. Obstet Gynecol 1997;89:291-296. 488. GERBER S, BONGIOVANNI AM, LEDGER WJ, WITKIN SS. Interleukin-1 beta gene polymorphism in women with vulvar vestibulitis syndrome. Eur J Obstet Gynecol Reprod Biol 2003;104:74-77. 509. FOSTER DC, BUTTS C, SHAH KV, WOODRUFF JD. Long term outcome of perineoplasty for vulvar vestibulitis. J Women's Health 1995;4(6):669-675. 510. GOESTSCH MF. Simplified surgical revision of the vulvar vestibule for vulvar vestibulitis. Am J Obstet Gynecol 1996;174(6):1701-1705 489. GERBER S, BONGIOVANNI AM, LEDGER WJ, WITKIN SS. Defective regulation of the proinflammatory immune response in women with vulvar vestibulitis syndrome. Am J Obstet Gynecol 2002;186:696-700. 490. JEREMIAS J, LEDGER WJ, WITKIN SS. Interleukin 1 receptor antagonist gene polymorphysism in women with vulvar vestibulitis. Am J Obstet Gynecol 2000;182:283-285. 491. ROBERT C, KUPPER TS. Inflammatory skin diseases, T cells and immune surveillance. NEJM 1999;341:1817-1828. 492. BORNSTEIN J, SHAPIRO S, RAHAT M, GOLDSHMID N, GOLDIK Z, LAHAT N, ABRAMOVICI H. Polymerase chain reaction search for viral etiology of vulvar vestibulitis syndrome. Am J Obstet Gynecol 1996;175:139-144. 493. SJOBERG I, LUNDQVIST EN. Vulvar vestibulitis in the north of Sweden. An epidemiologic case-control study. J Reprod Med 1997;42:166-168. 494. WILKINSON EJ, GUERRERO E, DANIEL R, SHAH K, STONE IK, HARDT NS, FRIEDRICH EG. Vulvar vestibulitis is rarely associated with human papillomavirus infection types 6, 11, 16 or 18. In J Gynecol Pathol 1993;12:344-349. 495. BAZIN S, BOUCHARD C, BRISSON J, MORIN C, MEISELS A, FORTIER M. Vulvar vestibulitis syndrome: an exploratory case-control study. Obstet Gynecol 1994;83:47-50. 974