Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions—Part II Sharon J. Parish, MD,1 Andrew T. Goldstein, MD,2 Sue W. Goldstein, BA,3 Irwin Goldstein, MD,4 James Pfaus, PhD,5 Anita H. Clayton, MD,6 Annamaria Giraldi, MD, PhD,7 James A. Simon, MD,8 Stanley E. Althof, PhD,9 Gloria Bachmann, MD,10 Barry Komisaruk, PhD,11 Roy Levin, PhD,12 Susan Kellogg Spadt, PhD, CRN, CSC,13 Sheryl A. Kingsberg, PhD,14 Michael A. Perelman, PhD,15 Marcel D. Waldinger, MD, PhD,16 and Beverly Whipple, PhD, RN, FAAN17

ABSTRACT

Introduction: Current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definitions of sexual dysfunction do not identify all sexual problems experienced clinically by women and are not necessarily applicable for biologic or biopsychosocial management of female sexual dysfunction. A unified nomenclature system enables clinicians, researchers, and regulatory agencies to use the same language and criteria for determining clinical end points, assessing research results, and managing patients. Aim: To develop nomenclature with classification systems for female sexual desire, arousal, and orgasm disorders with definitions pertinent to clinicians and researchers from multiple specialties who contribute to the field of sexual medicine. Methods: Key national and international opinion leaders diverse in gender, geography, and areas of expertise met for 2 days to discuss and agree to definitions of female sexual desire, arousal, and orgasm disorders and persistent genital arousal disorder. The attendees consisted of 10 psychiatrists and psychologists; 12 health care providers in specialties such as gynecology, internal medicine, and sexual medicine; three basic scientists; and one sexuality educator, representing an array of societies working within the various areas of sexual function and dysfunction. Main Outcome Measure: A unified set of definitions was developed and accepted for use by the International Society for the Study of Women’s Sexual Health (ISSWSH) and members of other stakeholder societies participating in the consensus meeting. Results: Current DSM-5 definitions, in particular elimination of desire and arousal disorders as separate diagnoses and lack of definitions of other specific disorders, were adapted to create ISSWSH consensus nomenclature for distressing sexual dysfunctions. The ISSWSH definitions include hypoactive sexual desire

Received May 2, 2016. Accepted September 25, 2016.

11

1

12

Departments of Psychiatry and Medicine, Weill Cornell Medical College, New York, NY, USA;

Department of Psychology, Rutgers University, Newark, NJ, USA;

13

2

The Center for Vulvovaginal Disorders, Washington, DC, USA;

3

San Diego Sexual Medicine, San Diego, CA, USA;

4 5

Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada;

6

7

Sexual Medicine, Alvarado Hospital, San Diego, CA, USA;

Departments of Psychiatry and Neurobehavioral Sciences and Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, USA;

Sexological Clinic, Psychiatric Center Copenhagen, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;

8 9

George Washington University, Washington, DC, USA;

Case Western Reserve University School of Medicine, Cleveland, OH; Center for Marital and Sexual Health of South Florida, West Palm Beach, FL, USA;

10

Department of Physiology, University of Sheffield, Sheffield, UK;

Female Sexual Medicine, Academic Urology Center for Pelvic Medicine, Bryn Mawr, PA; Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, PA, USA;

14

Departments of Reproductive Biology and Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA;

15

Department of Psychiatry, Reproductive Medicine and Urology, Weill Cornell Medicine; Human Sexuality Program, New York Presbyterian Hospital, New York, NY, USA;

16

Department of Pharmacology and Physiology, Drexel University School of Medicine, Philadelphia, PA, USA;

17

Rutgers University, New Brunswick, NJ, USA

Copyright ª 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jsxm.2016.09.020

Department of Obstetrics and Gynecology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA;

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disorder, female genital arousal disorder, persistent genital arousal disorder, female orgasmic disorder, pleasure dissociative orgasm disorder, and female orgasmic illness syndrome. Conclusion: Definitions for female sexual dysfunctions that reflect current science provide useful nomenclature for current and future management of women with sexual disorders and development of new therapies. J Sex Med 2016;13:1888e1906. Copyright  2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Key Words: Female Sexual Dysfunction; Nomenclature; Hypoactive Sexual Desire Disorder; Female Sexual Arousal Disorder; Female Genital Arousal Disorder; Female Orgasm Disorder; Persistent Genital Arousal Disorder

INTRODUCTION Several decades ago, experts believed that sexual dysfunctions in women and men were predominantly psychological; therefore, the mental health community represented by providers most interested in male and female sexual dysfunctions took responsibility for developing definitions of sexual dysfunctions. Historically, health care providers and researchers have relied on the evolving series of the Diagnostic and Statistical Manual of Mental Disorders (DSM).1 However, a resource that recognizes the biopsychosocial nature of sexual wellness and sexual health concerns is preferable for the contemporary management of female sexual dysfunctions (FSDs). The American Foundation of Urologic Disease funded a consensus conference in 1997 in an initial attempt to provide such a comprehensive guide. That consensus panel published their findings and recommendations in the Journal of Urology in 2000.2 Although the resulting publication continues to be cited in the literature, the nomenclature developed at that meeting is not universally used by the health care community when describing sexual problems. The fifth edition of the DSM (DSM-5) introduced a substantial modification of the nomenclature for women’s sexual dysfunction.3 The female nomenclature emphasized Basson’s4 “circular” model of FSD, rather than the previous linear model, and integrated the dysfunctions of hypoactive sexual desire disorder (HSDD) and female sexual arousal disorder (FSAD) into female sexual interest and arousal disorder (FSIAD). Although there is overlap between desire and arousal, combining the two diagnoses does not improve diagnostic accuracy. In addition, Sand and Fisher5 and Giraldi et al6 found that women identify with different sexual response models based on their sexual function at the time. The DSM-5 is a valuable resource when used for its intended purpose.3 It places less emphasis on parallel diagnoses of men’s and women’s sexual dysfunctions and has made significant changes to the FSD diagnoses.7 For instance, after having separate diagnoses for HSDD and FSAD, these two distinct but often co-presenting problems have been combined as FSIAD.3 In medicine, a constellation of symptoms is called a syndrome, but two diagnoses occurring concomitantly are still considered two different diagnoses. Combining them, as in the DSM-5, meaningfully limits their value for clinical management and/or clinical research. J Sex Med 2016;13:1888e1906

Nomenclature should be based on evidence from well-conducted research trials, case reports, and expert opinion. The committee on the incidence and prevalence on sexual dysfunctions from the Fourth International Consultation on Sexual Medicine (ICSM), held in June 2015, endorsed the widely agreed-to clinical principles regarding sexual desire and arousal in women. The committee report stated that HSDD should be maintained as an entity separate from FSAD. Incidence, prevalence, and risk factor data clearly show that delineating these two functions is supported by published evidence.8 Our review of the literature, research, and substantial clinical expertise suggests that the DSM-5 nomenclature omits distressing sexual conditions experienced by women, such as persistent genital arousal disorder (PGAD), female orgasmic illness (FOIS), and pleasure dissociative orgasm disorder (PDOD). The Fourth ICSM committee report supported these emerging conditions that have been established through case reports and expert opinion but are in need of further research.8 The objective of this initiative was to more clearly define nomenclature to establish a classification system for clinical care, research, and regulatory use in FSD. Clinicians could use this nomenclature for diagnostic criteria and as outcome measurements in the management of sexual problems. Devising a uniform language to be used by clinicians, researchers, and regulatory agencies also enables the development of clearly defined end points for clinical trials and for the development of pharmaceutical and device therapies. The International Society for the Study of Women’s Sexual Health (ISSWSH) initiated a nomenclature conference in December 2013. The mission of the nomenclature conference was to develop consensus among experts who are experienced in diagnosis, evaluation, treatment, and/or research in sexual medicine for a comprehensive, multidisciplinary, evidence-based nomenclature of standardized definitions for female desire, arousal, and orgasm disorders. Of note, sexual pain disorders8 and specifically vulvar pain disorders9,10 were addressed through separate consensus panels. These data-driven definitions of desire, arousal, and orgasm would (i) be applicable across disciplines and useful in clinical and research settings, (ii) serve as the basis of International Classification of Diseases (ICD) codes, and (iii) provide regulatory guidance for interventions aimed at the management of women’s sexual problems.

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METHODS In attempting to examine the need for diagnostic criteria developed by clinicians and researchers and to develop definitions, the ISSWSH convened an international panel of experts in desire, arousal, and orgasm disorders in women to develop a multidisciplinary, evidence-based nomenclature. Key opinion leaders were invited based on their contributions to the field of female sexuality and gender and geographic diversity. The members consisted of 10 psychiatrists and psychologists; 12 health care providers in non-mental health specialties including specialists in gynecology, internal medicine, and sexual medicine; three basic scientists; and one sexuality educator. These experts, who represented various stakeholder societies, met for 2 days in December 2013 in Annapolis, Maryland. The panel was chaired by Sharon Parish and co-chaired by Andrew Goldstein, then president-elect and president, respectively, of the ISSWSH. Funding for the meeting was provided by the ISSWSH with no external financial support. Each attendee was preassigned to a subcommittee chaired by a member of the nomenclature meeting steering committee: rationale, background, desire disorders, arousal disorders, or orgasm disorders. Attendees performed an extensive literature search in preparation for presentations made on the first day on the rationale of the need for new nomenclature; the background of current nomenclature including inherent problems; and current information regarding desire, arousal, and orgasm disorders. After completion of presentations followed by a question-andanswer period, subcommittees separated to discuss objectives, summative points, and controversies of each topic. Desire, arousal, and orgasm subcommittees presented the proposed nomenclature, definitions, and criteria to the entire assembly of experts. For completion of this report, an updated literature search through April 2016 was performed. All available evidence, including randomized controlled trials, retrospective studies, case reports, and expert consensus reports, were reviewed. In devising nomenclature for desire, arousal, and orgasm, levels of evidence (1e4) were used to substantiate grades of recommendation (AeD). When the only level of evidence available was expert panel consensus, it was noted as expert opinion. The term clinical principle, a concept widely accepted across disciplines when there might or might not be formal evidence, was applied when grades of recommendation could not be assigned.8 The consensus definitions with level of evidence and grade of recommendation are listed in Table 1.

Desire When Masters and Johnson published Human Sexual Inadequacy,11 a specific desire disorder was not included as a diagnostic category. However, in 1977, sexual desire was conceived of by Helen Singer Kaplan12 as an appetitive or pre-copulatory phase of the sexual response cycle, with its locus in the brain, initiating a cascade from sexual desire to sexual

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arousal to sexual activity to orgasm. Although sexual desire and arousal typically co-occur, Kaplan described a sexual desire disorder in which arousal sufficient for vaginal, clitoral, and labial engorgement still occurred in response to sexual stimulation but without a concomitant interest in participating in sexual activity. Subsequent empirical and theoretical work on sexual desire linked it to the conscious awareness of one’s sexual drive and/or an awareness of one’s responses to competent sexual stimuli or incentives13e16 and recognition of sexual activity as rewarding. As a construct, sexual desire is not related to a specific event and can occur spontaneously or in interaction with others. Many clinical and research attempts have been made to define sexual desire, and one way is to recognize that it is a composite experience consisting of a biological drive, an anticipatory motivational state, and a responsiveness to sexual stimuli. Sexual drive can be induced by adequate neurochemical action and/or nonsexual stimulation that increase responsiveness to one’s own sexual thoughts and fantasies.14,15 Sexual incentive stimuli, such as external erotic sensory cues or approach by another, can act together with sexual drive to intensify the emotional and behavioral responses toward those stimuli and increase one’s awareness of those responses.14e17 Sexual desire can become a wish to participate in sexual activity for the sake of physical pleasure, emotional intimacy, or other rewards. As such, sexual desire is linked to the reward value of sex and can be diminished if the intensity of the sexual reward(s) is decreased.18,19 Responsiveness to sexual stimuli can be described as the ability to respond with adequate sexual desire and arousal. This can be a combination of physical reactivity and cognitive processes influenced by inhibitory executive function, experience, and expectancy. Synonyms used in the scientific and popular literature include appetite, craving, drive, hankering, horny, hunger, interest, itch, lust, libido, motivation, passion, pining, and urge. As a primarily subjective experience, sexual desire or changes in interest are not necessarily accompanied by observable changes in sexual behavior or frequency. Because sexual desire can be described in many ways, it is often difficult to assess and distinguish “normal” levels of desire from “abnormal” levels, and as such, low or hypoactive desire can be difficult to define in a singular way. Low sexual desire can manifest as partial or complete loss of sexual drive, interest, motivation, receptivity, thoughts, fantasies, and the wish to participate in sexual activity. It also can be experienced as an inability to sustain sexual interest during sexual activity. It can be generalized to all partners and sexual activity or situational in response to a particular partner or type of sexual activity. It can be acquired after an event or series of events, a medical intervention such as surgery, or with use of medications, or be experienced lifelong without any obvious psychosocial or biological event or etiology. With acquired, generalized HSDD, by definition women have experienced healthy, adequate desire and are distressed to have lost it.20 Clinical definitions of disordered low sexual desire have varied widely. The 10th revision of the ICD21 and the fourth text J Sex Med 2016;13:1888e1906

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Table 1. International Society for the Study of Women’s Sexual Health sexual disorders nomenclature and definitions including level of evidence Hypoactive sexual desire disorder (grade ¼ B, level of evidence ¼ 2e3) Manifests as any of the following for 6 mo: Lack of motivation for sexual activity as manifested by Decreased or absent spontaneous desire (sexual thoughts or fantasies) Decreased or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity Loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is not secondary to sexual pain disorders and is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry Female genital arousal disorder (grade ¼ B, level of evidence ¼ 2e3) Defined as the inability to develop or maintain adequate genital response for 6 mo, including Vulvovaginal lubrication Engorgement of genitalia Sensitivity of genitalia associated with sexual activity Disorders related to: Vascular injury or dysfunction and/or Neurologic injury or dysfunction Persistent genital arousal disorder (expert opinion) Characterized by persistent or recurrent, unwanted or intrusive, distressing feelings of genital arousal, or being on the verge of orgasm (genital dysesthesia), not associated with concomitant sexual interest, thoughts, or fantasies for 6 mo. Could be associated with: Limited resolution, no resolution, or aggravation of symptoms by sexual activity with or without aversive and/or compromised orgasm Aggravation of genital symptoms by certain circumstances Despair, emotional lability, catastrophizing, and/or suicidality Inconsistent evidence of genital arousal during symptoms Female orgasm disorders (grade ¼ B, level of evidence ¼ 2e3) Characterized by a persistent or recurrent distressing compromise of orgasm frequency, intensity, timing, and/or pleasure associated with sexual activity for 6 mo: Frequency: orgasm occurs with decreased frequency (diminished frequency of orgasm) or is absent (anorgasmia) Intensity: orgasm occurs with less intensity (muted orgasm) Timing: orgasm occurs too late (delayed orgasm) or too soon (spontaneous or premature orgasm) than desired by the woman Pleasure: orgasm occurs with absent or decreased pleasure (anhedonic orgasm, pleasure dissociative orgasm disorder) (expert opinion) Female orgasmic illness syndrome (expert opinion) Characterized by peripheral and/or central aversive symptoms that occur before, during, or after orgasm not related, per se, to a compromise of orgasm quality

revision of the DSM (DSM-IV-TR) of the American Psychiatric Association22 described HSDD as a lack or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulties and is not explained by another mental disorder (eg, depression), drug use (prescription or illicit), or another known medical condition. When HSDD is due exclusively to a general medical condition or substance (medication or drug of abuse), it is considered HSDD because of that condition. The third edition of the DSM referred to it as “inhibited sexual desire.”23 The recent DSM-5 combined sexual arousal and desire disorders for women into a single entity, FSIAD, thus eliminating HSDD and sexual arousal disorder in women and adding more explicit criteria, including experiencing the disorder 75% to 100% of the time and a required minimum duration of occurrence of at least 6 months.3 In addition to absent or decreased J Sex Med 2016;13:1888e1906

sexual interest and erotic thoughts or fantasies, four new criteria were added: absent or decreased (i) initiation of sexual activity or responsiveness to a partner’s attempts to initiate it, (ii) excitement and pleasure, (iii) response to sexual cues, and (iv) sensations during sexual activity, whether genital or non-genital. Three of six criteria are required for diagnosis. The qualification of interpersonal difficulties was removed from the diagnostic definition. Furthermore, traditional specifiers were included to more fully describe the dysfunction (lifelong vs acquired and generalized vs situational); and possible etiologic factors were introduced, including partners, relationships, individual vulnerability, cultural or religious, and medical conditions, acknowledging the many biopsychosocial factors that can influence women’s sexual desire. However, if non-sexual mental disorders, substance or medication use, another medical condition, interpersonal factors, or other sexual dysfunctions fully explain the

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symptoms of low desire and arousal, then a diagnosis of FSIAD would not be made.3 Definition Issues Among the reasons for the new diagnostic name and criteria were clinical and experimental observations that sexual arousal and desire typically co-occur in normative sexual responding24e26 and that women therefore might experience difficulties in arousal and desire to varying degrees, that is, a lack of perceived genital sexual arousal (ie, vasocongestion) when it is present.27 The definition and criteria were not changed for men, nor were data reported by the DSM-5 workgroup as to why the term interest was any better than desire at predicting diagnostic homogeneity or successful clinical interventions. The term desire has been operationally defined in a number of studies (eg, those listed earlier) using variants of the DSM-IV-TR criteria, whereas the term interest has not been studied on its own or has not been studied in anticipation of the changes in the DSM-5 with reference to desire in a proposed “sexual desire and interest disorder.”28 Sexual desire and interest disorder was defined by “low sexual desire, absent sexual fantasies, and a lack of responsive desire,”27 whereas for HSDD the DSM-IV criteria were used as the definition. Accordingly, women with sexual desire and interest disorder had lower ratings of sexual desire and arousal compared with women diagnosed with HSDD, suggesting greater severity when more criteria and longer duration of symptoms are required for diagnosis. However, it is unclear how the term interest is interpreted by women, or indeed whether it carries the same subjective meaning or statistical weighting (eg, in a factor analysis) as desire. Colloquially, it seems that interest is a less intense state than desire. The adoption of new and as yet non-validated terminology could render previous studies of therapeutic efficacy (psychological, pharmacologic, or device interventions) null and void given the introduction of a new terminology. If the terms are equal, then why change them? However, there is a more insidious problem related to the stringency of the diagnostic criteria in the previous and current incarnations of the DSM, namely false negatives in which women would not be identified or receive treatment because of the inability to meet required diagnostic criteria.24,29 One recent study assessed differences in diagnostic power and subsequent assignment to groups between the DSM-IV-TR and DSM-5 criteria for sexual arousal and desire disorders. In a random sample of 227 women and men with some form of arousal and/or desire complaint, the use of operationalized DSM-IV-TR criteria led to the exclusion of more than 75% of those reporting difficulties.24 The main reason for exclusion in that study was a failure to meet at least one diagnostic criterion. The application of the DSM-5 criteria was even more restrictive and led to the exclusion of all but four men (of 113 men) and one woman (of 114 women) using the originally proposed four-symptom

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criteria and all but four men and five women using the revised three-symptom criteria. Subsequent cluster analyses in that study supported a distinction between desire and genital arousal difficulties, although these analyses showed that different groups with one or two sets of symptoms existed. Clearly, then, the stringent diagnostic criteria of the DSM-5 end up being unduly restrictive and do not capture the full range of many sexual difficulties, a problem especially pertinent to the diagnosis of sexual desire disorders. These findings are supported in baseline assessments for a clinical trial (exploratory or post hoc analyses) of premenopausal women diagnosed with HSDD and/or FSAD (HSDD primary) using DSM-IV-TR criteria.29,30 Diagnostic Revision We argue for a broadening and simplification of the diagnostic criteria and a return to the previous diagnostic label for which there is a large body of empirical experimental and clinical evidence. HSDD manifests as any of the following for a minimum of 6 months:  Lack of motivation for sexual activity as manifested by: B Decreased or absent spontaneous desire (sexual thoughts or fantasies); or B Decreased or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity;  Loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is not secondary to sexual pain disorders;  And is combined with clinically significant personal distress that includes frustration, grief, guilt, incompetence, loss, sadness, sorrow, or worry (Table 1). The experience and impact of symptoms of HSDD as a whole should be rated by the person affected as mild, moderate, or severe. This definition of HSDD can be applied in a biopsychosocial context and therefore be used in the somatic and psychiatric diagnostic systems. It is critical to identify the temporal relation of etiologic and risk factors of low or diminished desire, which could be acquired or lifelong, but should be generalized when considering current pharmacotherapies. If the diminished desire is situational, then the locus of the desire disorder should be considered outside the woman, which can have management implications. This would include situations in which the low desire is secondary to physical and/or emotional abuse, dissatisfaction with one’s partner, including the partner’s sexual dysfunction, or the intrusion of life stressors that can be affected by psychological and/or lifestyle changes. Such situational loss of desire could be an understandable response to a stress, distressing to the woman, and be disserving of intervention, but this is not generalized HSDD per se. J Sex Med 2016;13:1888e1906

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Known Etiologies and Risk Factors Etiologic and risk factors for HSDD include biological, psychological, and social. The most prominent are discussed below (Table 2).

Hormonal changes. Steroid hormone actions in the hypothalamus and limbic system prime the brain to be selectively responsive to sexual incentives and can create a state of “spontaneous” sexual drive and anticipatory motivation for sexual interaction and gratification.34e37 Such priming involves molecular actions that result from the binding of androgens, estrogens, and progestins to specific hormone receptor complexes and lead to the synthesis of different neurotransmitters and transmitter receptors. This creates a neurochemical state in which sexual stimuli are attended to selectively and are more likely to induce sexual responding.15,34 Accordingly, sexual desire and the emotional response to sexual stimuli change across the menstrual cycle37e39 as demonstrated by midcycle peaks (corresponding to ovulation) of behavioral representation of desire in animal models.34,40 Changes in cognitive function and awareness of sexual desire and arousal as a function of the ovulatory menstrual cycle have been established.41e45 Changes in cortical eventrelated potentials in frontal, mid-parietal, and occipital poles occur in premenopausal women during ovulation that are indicative of greater attention to sex-related stimuli.46 Blood oxygenation level-dependent contrast images taken by functional magnetic resonance imaging in premenopausal women during the luteal phase compared with preovulatory phases of the cycle have shown a pattern of activation consistent with increased attention, cognitive arousal and excitement, and pleasure derived from external sexual stimuli.14,47,48 Natural or surgically induced states of hypogonadism in animals and humans are typically associated with a decreased responsivity to sexual stimuli34,49e51 and a significant loss of appetitive sexual desire and behavior. Many individuals presenting with decreased sexual desire have concomitant endocrine dysregulation, including decreased androgens and hyperprolactinemia.52 Pathophysiologic ovarian and/or adrenal function can result in androgen deficiencies in premenopausal women.31 The measurement of total and free testosterone levels during non-ovulatory phases of the cycle is not indicative of the pulse of testosterone during ovulation, and it cannot be used to predict the effects of testosterone or other androgens in the brain. Although some studies have failed to demonstrate an association between desire and circulating androgens,53,54 positive correlations have been reported between circulating free testosterone and androstenedione and the sexual desire domain of the Female Sexual Function Index.55

Inter- and intrapersonal factors. Studies have shown that adverse relationship factors and having a partner are correlated to low sexual desire.32,33 These findings could reflect the reality that women are more confronted with their low desire when being in a relationship vs no relationship and therefore more distressed. J Sex Med 2016;13:1888e1906

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Table 2. Known etiologies and risk factors of hypoactive sexual desire disorder Hormonal changes Androgens Hypothalamic amenorrhea Premature ovarian failure Acquired immunodeficiency wasting syndrome Adrenal insufficiency Hypopituitarism31 Pituitary tumors After oophorectomy Estrogens Progestins Prolactin Interpersonal factors Life situation and social status Married or partnered women32 Partner sexual dysfunction33 Medications Psychopharmacologic Antidepressants Antipsychotics Barbiturates Benzodiazepines Hypnotics Hormonal Oral contraceptives Gonadotropin-releasing agonists and analogues Antiandrogens Antiestrogens Other medications Cholesterol-lowering agents b-Blockers Spironolactone Chemotherapeutics Substances of abuse Legal Controlled Illegal Medical and psychiatric conditions Diabetes Urinary incontinence Neurologic disease Cancer Depression

It can be difficult to determine whether transient sexual dissatisfaction led to relationship problems or relationship problems and maladjustment led to sexual problems. When comparing women with HSDD to women without HSDD, women with HSDD report less attraction and emotional closeness to their partner, more dissatisfaction with resolution of conflicts, poorer dyadic adjustment, and might describe that relationship factors were associated with their sexual

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problems.33,56,57 However, if relationship factors appear to be the cause of the low desire, it is important to note this would not be diagnosed as generalized HSDD. Intrapersonal factors also affect desire: personality traits of extraversion, openness to experience, emotional stability, conscientiousness, and positive coping strategies have correlated positively with sexual desire.58

Medications. Several medications affect sexual desire negatively through actions on central neurotransmitter and neuroendocrine systems. Most prominent are psychopharmacologic agents affecting the serotonergic, dopaminergic, and prolactin systems.59e61 These medications can shift the balance between sexual excitation and inhibition by enhancing descending inhibitory outflow (eg, selective serotonin reuptake inhibitors) or by blunting sensory awareness and the autonomic responses to sexual stimulation.14 Medications with effects on the endocrine system can exert their effect by influence on the ovaries, pituitary, and hypothalamus directly or by negative feedback, leading to a decrease in circulating testosterone and/or estradiol.62 Medications treating chronic illness also can negatively affect desire.62e64

Medical and psychiatric conditions. Different medical and psychiatric conditions can adversely affect sexual desire; however, the evidence for the effect of different acute and chronic conditions varies.62,64 Depression is the most important clinical condition affecting sexual desire, and this relation is bidirectional.65 Although medications used to treat depression can affect desire through shared underlying mechanisms, several studies have demonstrated that the severity of depression might have a more significant adverse effect on desire than antidepressant medication side effects.65e67 Also, studies have reported that changes in depression severity correspond to same-day variations in sexual desire.68,69

Strengths and limitations of desire consensus definitions. The strength of the new definition of HSDD is to preserve distinct and specific criteria for clinical diagnosis and guide therapeutic end points in research trials. Limitations include the need for validation of proposed diagnostic criteria and establishment of conventions for terminology, definitions, and criteria for placebo or sham arms in clinical trials. Also needed are end points in evaluations of potential medications and psychotherapy interventions, the effects of the combination of medication and standardized psychotherapy in sexual desire disorders, and the usefulness of biologic measurements in diagnosis of disorders of sexual desire.

Arousal Traditionally, female sexual arousal has been defined by the physiologic genital responses that occur during an anticipatory period before sexual activity and during sexual activity up to the

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point of orgasm.70e72 Physical changes such as increased vulvovaginal lubrication, engorgement of the genitalia, and increased sensitivity of the genitalia are just some of the hallmark changes associated with female sexual arousal. In addition, non-genital changes are included in definitions of female sexual arousal. The genital response of female sexual arousal72 depends on normal functioning of the endothelium in the hypogastriccavernosal vascular bed in conjunction with the pelvic parasympathetic nerve.73 Definition Issues Different methodologies have been used to objectively measure genital changes, including heated oxygen electrode,74 thermography, impedance plethysmography, photoplethysmography, and laser Doppler.75 Some definitions of arousal also include the subjective awareness and enjoyment of the genital and extragenital changes occurring before and during sexual activity. However, there is controversy as to whether subjective awareness of the physical changes of arousal is just one aspect of sexual desire. In addition, there is evidence that in some women, or in some situations, there is a “disconnect” between the perceived subjective awareness of arousal and the presence, or absence, of genital vasocongestion. For example, women exposed to descriptions of sexual assault showed evidence of genital vasocongestion.76,77 Also, genital arousal does not necessarily correspond to a woman’s stated sexual preference because lesbian and heterosexual women show substantial genital vasocongestion to films of preferred and non-preferred genders.78

Female sexual arousal disorder. Definitions of altered arousal (ie, FSAD) have varied greatly. The most widely used and studied definition of FSAD was from the DSM-IV-TR published in 2000: Persistent or recurrent inability to attain, or to maintain until completion of the sexual activity an adequate lubrication-swelling response to sexual excitement. The disturbance causes marked distress or interpersonal difficulty. The sexual dysfunction is not better accounted for by another Axis I disorder (except another sexual dysfunction) and is not due to the direct physiological effects of substance abuse or a general medical condition.22 This definition focused solely on the genital response, did not mention any extragenital responses, and excluded issues related to any cognitive or emotional response to arousal. This is in contrast to the previous DSM-III definition of “inhibited sexual excitement,” in which the “excitement phase” was described as consisting of “a subjective sense of sexual pleasure and accompanying physiological changes.”79 The omission of the subjective component of arousal was addressed in the text of the DSM-IV-TR in which it is stated, “The individual with Female Sexual Arousal Disorder may have little or no subjective sense of sexual arousal.” J Sex Med 2016;13:1888e1906

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To address “shortcomings of the traditional nosology of women’s sexual disorders,”27 in 2002 the American Urological Association (AUA) conference examined the definition of FSAD and proposed three separate types of dysfunctional arousal.79

Genital sexual arousal disorder. “Complaints of absent or impaired genital sexual arousal. Self-report may include minimal vulvar swelling or vaginal lubrication from any type of sexual stimulation and reduced sexual sensations from caressing genitalia. Subjective sexual excitement still occurs from non-genital sexual stimuli.”79

Subjective 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.”79 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 (vulvar swelling, lubrication).”79 Despite the apparent superiority of the proposed AUA definition, in 2010 the arousal subgroup of the International Society for Sexual Medicine standards committee examined all FSAD studies conducted after the AUA proposal and concluded that “only two studies have investigated a distinction between the described subtypes of FSAD, and the results from these studies do not completely match the expected outcomes.”70 In 2013 the DSM-5 was released by the American Psychiatric Association with a combined diagnosis of the DSM-IV-TR definitions of FSAD with HSDD. The rationale for creating an amalgam of FSAD and HSDD was supported by studies that showed a high comorbidity between FSAD and HSDD27 and other studies that showed that many women did not differentiate between sexual arousal and desire.80e84 There have been proposals of different models of sexual desire and motivation that closely interact with arousal. Moreover, the new definitions of sexual desire highlight its interrelation with arousal.82,85 However, as mentioned earlier, there are other studies that have clearly shown that at least vasocongestion and its accompanying lubrication are distinct from subjective arousal and sexual desire.83 Specifically, genital arousal appears to exist if the amount of vaginal lubrication is distinct from the amount of perceived (subjective) arousal.76,86 It also has been argued that the mechanism for lubrication during sexual arousal is just an evolutionary mechanism designed to prevent genital trauma during assault. In the context of rape, subjective sexual arousal is clearly not present, yet genital arousal might be present.87

Physiologic response of genital arousal. Female genital arousal is a physical state arising from the processing of physical J Sex Med 2016;13:1888e1906

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and non-physical (emotional) stimuli leading to increased activity in the central and peripheral nervous systems. The increased sympathetic nervous system activity leads to an increase in vascular blood flow to the vulva (including the clitoris) and vagina, resulting in several different genital responses including engorgement of the genitals, increase in temperature of the genitals, and an increase in lubricating secretions in the vulva and vagina. The sacral parasympathetic innervation also is a contributor to female genital engorgement and vaginal lubrication. These secretions are a combination of mucin released from androgen-dependent glands of the vulva (Bartholin, Skene, and minor vestibular glands) and a transudate of blood serum that leaks through aquaporin channels in the vaginal mucosa.88 In addition, there is lengthening of the vagina89 and relaxation of the pelvic floor muscles. Extragenital arousal includes erection of the nipples, flushing of the skin, increased heart rate, increased blood pressure, and increased respiration rate. Diagnostic Revision Female genital arousal disorder (FGAD) is defined as the inability to develop or maintain adequate genital response including vulvovaginal lubrication, engorgement of the genitalia, and sensitivity of the genitalia associated with sexual activity for a minimum of 6 months. Subcategories of this disorder are related to (i) vascular injury or dysfunction and/or (ii) neurologic injury or dysfunction (Table 1). Although there is significant overlap in the presentation of and treatments for FGAD and other sexual dysfunctions and other medical disorders, FGADs are a separate and distinct entity and should be classified as such. Traditional specifiers (ie, causing or not causing significant intra- or interpersonal distress) apply to the aforementioned subcategories. Based on expert opinion, FGAD is usually acquired and generalized. Arousal can be associated with non-genital responses such as hardening and erection of the nipples, flushing of the skin, increased heart rate, increased blood pressure, and a more rapid respiration rate. If a woman’s difficulty with genital arousal is due to insufficient stimulation, then FGAD should not be diagnosed. Note that vulvovaginal atrophy, vulvovaginal infection or inflammation, inflammatory disorders of the vulva or vagina, vestibulodynia, and clitorodynia should be excluded before the diagnosis of FGAD is made. General criteria for these diagnoses are listed in Table 3.

Diagnosis. The diagnosis of FGAD is made primarily by history and physical examination. The examination is used to rule out the exclusionary conditions listed earlier. Additional clinical findings in research studies that are suggestive of FGAD are a lack of swelling of the labia and/or clitoral tumescence after adequate self-stimulation, no increase in vaginal transudate after self-stimulation, and no increase in vaginal pH after selfstimulation. Additional laboratory testing that can be used for criteria to diagnosis FGAD include decreased pudendal nerve

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Table 3. Exclusionary criteria for female genital arousal disorder Vulvovaginal atrophy Vaginal pH > 5.0 Loss of vaginal rugae Increased proportion of intermediate and parabasal cells Decrease in superficial cells on wet mount from upper third of vagina Erythema, tenderness of vestibular glands Low estradiol level Low free testosterone level Vulvovaginal infection or inflammation Increased pH > 4.0 Increased leukocytes on wet mount Hyphae, yeast spores Trichomonads Positive whiff test result Clue cells > 10% on wet mount Cervicitis Inflammatory disorders of vulva or vagina Lichen sclerosus Lichen planus Plasma cell vulvitis Mucous membrane pemphigoid Desquamative inflammatory vaginitis Sjögren syndrome Contact dermatitis Allergic vaginitis Semen allergy Painful episiotomy scar Vulvar granuloma fissuratum Evidence of vulvar scarring Fissures Lichenification Tearing at posterior fourchette Scar tenderness Vestibulodynia or clitorodynia Allodynia of vulvar vestibule Allodynia of clitoris

terminal latency testing or no change in vaginal pulse amplitude using photoplethysmography, resistance using impedance plethysmography, vulvar blood flow as measured by thermography, vaginal blood flow as measured by pulse Doppler, or blood flow as measured by a heated vaginal electrode. Data regarding prevalence are unknown because this new definition excludes any subjective arousal components. In addition, diagnostic questionnaires such as the Female Sexual Function Index have not been validated in this new FGAD diagnosis or domain. However, earlier studies have shown female sexual arousal and lubrication problems are prevalent in 8% to 28% of sexually active women. Evidence shows that as women age beyond the menopausal transition, insufficient lubrication for comfortable vaginal penetration appears to be more prevalent.90

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Known Etiologies and Risk Factors Robust biological evidence supports the physiologic rationale for the category FGAD. Risk factors for FGAD are categorized as vascular, neurologic, and pelvic radiation or surgery. Table 4 presents detailed information about the relation between these physical conditions and genital dysfunction.91e116 The relation between cardiovascular health and female sexual function and dysfunction is extensively examined in the summary of the third Princeton Consensus conference. The review of this consensus conference by Miner et al73 provides a very thorough review of the literature that shows hypertension, hyperlipidemia, metabolic syndrome, obesity, diabetes, and coronary artery disease increase the risk of FSAD (DSM-IV-TR definition). Metabolic syndrome is a multifactorial disorder that includes concomitant impaired glucose tolerance and diabetes, central obesity, high triglyceride levels, low levels of high-density lipoprotein, and hypertension. This group of risk factors increases the relative risk for developing coronary artery disease, diabetes, stroke, and other health problems. Disorders that can adversely affect the central nervous system and peripheral nervous system such as diabetes and multiple sclerosis also can affect female sexual arousal. Research findings have suggested that sympathetic nervous system activation by exercise and sympathetic nervous system activating medication can facilitate the early stages of female sexual arousal, whereas drugs that cause sympathetic nervous system inhibition can inhibit female sexual arousal and contribute to the symptoms of FGAD.102 There are discrepant data for pelvic irradiation and pelvic surgery. Pelvic irradiation can cause decreased genital blood flow from damage to small blood vessels and nerve endings. Although validated questionnaires show a decrease in arousal and lubrication domains after irradiation, small studies have failed to show changes by vaginal pulse amplitude.103e106 Pelvic surgery has been reported as having mixed effects on arousal and overall sexual function. These procedures include radical hysterectomy with or without irradiation, total abdominal hysterectomy, pelvic organ prolapse surgery, and trachelectomy.

Strengths and limitations of arousal consensus definitions. One scientific strength of the new definition of FGAD is that there are a wide variety of instruments, as listed earlier, showing temperature changes and vascular flow and cortical evoked potentials elicited from the dorsal nerve of the clitoris that can be used to objectively show this disorder. These objective measurements will clearly support experimental protocols for pharmacologic and non-pharmacologic interventions. Moreover, this definition completely excludes the central arousal issue (ie, subjective arousal disorder) that was controversial (and convoluted) in prior definitions of FSAD and thus strengthens the definition of FGAD and HSDD discussed in this document. One limitation of this definition is that the aforementioned laboratory instruments used to measure FGAD are not generally J Sex Med 2016;13:1888e1906

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Table 4. Studies correlating risk factors and etiologies for female arousal disorder Etiology

Supporting evidence

CAD Diabetes

Decreased sexual arousal (FSFI) in women with CAD by angiography vs without CAD91 Smooth muscle cell structural abnormalities (increased glycogen deposits, cytoplasmic vacuoles, density of collagen fibers, infolded cell borders) in biopsy specimens of clitoral cavernosal tissue of premenopausal diabetic women92 Increased sexual dysfunction vs controls in 100 diabetic Iranian women, worsening based on duration of disease93 Increased prevalence of FSAD with increased glycated hemoglobin, body mass index, duration of diabetes in premenopausal women with type 2 diabetes94 More FSAD (FSFI) in 441 hyperlipidemic women without cardiovascular disease (32%) vs 115 normolipidemic women (9%)95 Low sexual arousal independent risk factors: HDL, cholesterol, increased triglyceride levels95 Sexual dysfunction (FSFI) reported in 71 premenopausal Turkish hypertensive women without additional chronic disease (90%) vs 85 normotensive premenopausal women (41%)96 Lower sexual arousal (FSFI) in women with metabolic syndrome than in normal women97 Prevalence of FSAD (FSFI) higher in 103 postmenopausal women with metabolic syndrome vs 105 healthy postmenopausal controls98 Difficulty with sexual arousal in women with multiple sclerosis (19.5%)99 Decreased amplitude of cortical evoked potentials of dorsal nerve of clitoris, arousal and orgasm in women with multiple sclerosis100 Increase in sexual arousal difficulties in women with multiple sclerosis (Multiple Sclerosis Intimacy and Sexuality Questionnaire-19, Arizona Sexual Experiences Scale)101 Increased arousal (measured by self-report, vaginal photoplethysmography) from exercise-induced SNS activation with concomitant VSS but no change without VSS102 Arousal (vaginal photoplethysmography) facilitated by pharmacologically induced SNS activation with concomitant VSS but no change in arousal by self-report102 Decreased arousal (measured by self-report, vaginal photoplethysmography) by pharmacologically induced SNS inhibition when administered after exercise-induced SNS activation with concomitant VSS102 No difference in VPA (during photoplethysmography) in women exposed to pelvic irradiation103,104 Decreased arousal and lubrication domain scores (FSFI) after irradiation105,106 Decreased arousal from radical hysterectomy with or without adjuvant pelvic irradiation107 Nerve-sparing techniques disrupt vaginal blood flow (VPA) less than traditional radical hysterectomy techniques108 Frequency of sexual intercourse in women undergoing uterus-sparing trachelectomy for early-stage cervical cancer approached that of healthy controls 1 y after surgery but arousal (FSFI) remained persistently worse109 Sexual arousal improved after surgery for pelvic organ prolapse including non-radical hysterectomy110,111 Sexual function worsened from increased dyspareunia, not decreased arousal, when mesh used in pelvic organ prolapse surgery112 Arousal not worsened with non-radical total abdominal hysterectomy for benign disease in most cases, although some women reported worsened sexual response113 No improvement in sexual arousal in supracervical hysterectomy114 Sexual function after laparoscopic uterosacral nerve ablation for chronic pelvic pain not studied115,116

Hyperlipidemia

Hypertension Metabolic syndrome

Multiple sclerosis

SNS activation and inhibition

Pelvic irradiation Pelvic surgery

CAD ¼ cardiovascular arterial disease; FSAD ¼ female sexual arousal disorder; FSFI ¼ Female Sexual Function Index; HDL ¼ high-density lipoprotein; SNS ¼ sympathetic nervous system; VPA ¼ vaginal pulse amplitude; VSS ¼ visual sexual stimulation.

used by most practitioners; however, in clinical practice, the diagnosis can be made reasonably well with a history and physical examination. Another limitation is that the symptoms of FGAD are similar to or overlap with the symptoms of genitourinary syndrome of menopause (previously known as vulvovaginal atrophy); therefore, the diagnosis can be made only in a woman whose symptoms related to gonadal hormonal loss (in the external vulva, clitoris, vulvar vestibule, and vagina) are adequately managed. J Sex Med 2016;13:1888e1906

Persistent Genital Arousal Disorder Distressing difficulties with disorders of excess arousal exist. PGAD is not included in the DSM-IV-TR or DSM-5 classification systems for FSDs. Definition Issues PGAD is characterized by persistent or recurrent, unwanted or intrusive, distressing feelings of genital arousal or being on the verge of orgasm (genital dysesthesia) not associated with

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concomitant sexual interest, thoughts, or fantasies for a minimum of 6 months (Table 1). PGAD can be lifelong or acquired, generalized or situational, and associated with the following characteristics:  Limited resolution, no resolution, or aggravation of symptoms by sexual activity with or without aversive and/or compromised orgasm or impaired orgasm frequency, intensity, timing, and/or pleasure;  Aggravation of genital symptoms by certain circumstances (sitting, driving, listening to music, general anxiety, stress or nervousness);  Despair, emotional lability, catastrophizing, and/or suicidality;  Inconsistent evidence of genital arousal on physical examination during symptoms (lubrication, swelling of clitoris or labia). When PGAD occurs concomitantly with complaints of overactive bladder and/or restless leg syndrome, it can be considered restless genital syndrome.117 The diagnoses PGAD and restless genital syndrome are based on expert opinion and require further research. Known Etiologies and Risk Factors There are currently no prevalence data on PGAD. It can result from a peripheral trigger from increased genital engorgement; a central trigger from the perception of increased genital engorgement, such as from increased sensitivity of the external genitalia; Tarlov (perineurial) cysts, which compress and irritate the genital sensory nerve roots at their site of entry to the spine at the sacral level118,119; and/or other factors (eg, cognitive)120 as yet undetermined. The pathways by which the PGAD-inducing sensory messages access the brain remain unknown. Clinical conditions observed in women presenting with PGAD include peripheral genital pathologies,118,121e125 spinal cord and brain disorders,126e129 and psychological conditions (Table 5).120,126e128

Orgasm An operational definition of orgasm is: “An orgasm in women is a variable transient peak sensation of intense pleasure creating an altered state of consciousness, usually with an initiation accompanied by involuntary, rhythmic contractions of the pelvic striated circumvaginal musculature, often with concomitant [vaginal], uterine and anal contractions, and myotonia that resolves the sexually induced vasocongestion [sometimes only partial] and myotonia, generally with an induction of well-being and contentment.”130 Physiology of Orgasm Characterizing the physiology of female orgasm is important, but there have been limited research studies; and the physiologic changes that occur in women just before, during, and immediately after orgasm have not been fully identified. Just before an

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Table 5. Clinical observations associated with persistent genital arousal disorder Peripheral genital pathologies Vestibulodynia, clitorodynia Vulvovaginal atrophy Injury to, irritation of pudendal nerves that transmit pain, other sensations Abnormal tissue response to candida infection, allergy Dermatologic conditions Vulvar granuloma fissuratum Pathology of periurethral glans Pelvic congestion syndrome, arteriovenous malformations S2eS4 Tarlov cyst High-tone pelvic floor dysfunction Rectal diverticulum Spinal cord or brain pathologies Central dysregulation problems Trazodone use Abrupt discontinuation of antidepressant (eg, selective serotonin reuptake inhibitor) Tumor, mass, cyst, aneurysm Herniated disc Cerebral vascular accident Psychologic conditions Stress Worry Panic disorder Anxiety

orgasm is initiated, the highest peak levels of heart rate, blood pressure, and respiration are observed. The internal and external genitalia undergo physiologic changes.131e136 Before orgasm, physiologic changes include tumescence and color change from pink to deep red in the labia minora; tumescence in the vaginal introitus, glans clitoris, and corpora cavernosa of the clitoral shaft and crura, periurethral glands including the tissue of the urethral meatus, the Halban fascia, anterior vaginal wall structures including the periurethral, prostatic, and G-spot area tissue; lubrication by neurogenic-induced transudation across the vaginal epithelium; and smooth muscle relaxation of the vaginal wall.131e136 Several of these changes before orgasm have been characterized by magnetic resonance imaging. During orgasm, there are repeated pelvic muscle contractions of varying intensity and duration.137 In some women, these are intense and repetitive and can last for several seconds; in others, they are weak, of mild intensity, and of limited duration and repetition; and in others, pelvic floor contractions are not perceived during orgasm.138e143 Sensitivity to pain also is markedly decreased at orgasm.144 Brain imaging by function magnetic resonance imaging or positron emission tomography has characterized regions activated, inhibited, or unchanged during orgasm by imaging J Sex Med 2016;13:1888e1906

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increases or decreases in regional brain blood flow.145e148 There is no current consensus as to the specific constellation of brain regions activated or inactivated during orgasm in women.145e147,149e151 Immediately after orgasm, there are rapid decreases in heart rate, blood pressure, and respiration. Changes in genitalia include detumescence or decongestion (sometimes only partially) and return of the labial color. Enhanced neurogenic lubrication stops and excess fluid is reabsorbed osmotically concomitantly with the active lumen-to-blood Naþ transport of the vaginal epithelium136,152 returning it to the “just-moist condition.” DSM-IV-TR and DSM-5 Definitions In the DSM-IV-TR, female orgasmic disorder (FOD) is considered a female sexual disorder in which women have “persistent or recurrent delay in, or absence of orgasm after a normal sexual excitement phase.” Women with FOD experience negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. FOD is not better accounted for by a general medical or psychiatric condition (ie, anxiety and depression) and is not due exclusively to the direct physiologic effects of a substance or medication.22 In the DSM-5, FOD is considered a female sexual disorder with the presence of the following “on all or almost all (75%e100%) occasions of sexual activity: 1. Marked delay in, marked infrequency of, or absence of orgasm and 2. Marked reduced intensity of orgasmic sensations.” Symptoms persist a minimum of 6 months and are not better explained by a nonsexual mental disorder or consequence of severe relationship distress or other significant stressors and not due to effects of substance or medication or other medical conditions.3 In summary, combining these DSM system classifications, FOD has been defined by compromises in orgasm quality relating to (i) absence of orgasm, (ii) delay in orgasm, (iii) infrequency of orgasm, or (iv) decreased intensity of orgasm, after sufficient sexual stimulation, causing personal distress. However, sexual medicine health care providers manage women who complain of far more broad, diverse, and differing orgasmic complaints than those represented in the DSM-IV-TR or DSM-5 system. These definitions are inadequate and do not characterize and include numerous kinds of bothersome and distressing FODs seen and managed by these providers. A more inclusive, user-friendly classification of women with distressing orgasm is required. Definition Issues As noted earlier, some orgasm classifications are currently missing from the DSM. Biopsychosocial-oriented sexual medicine providers manage women distressed with compromises in orgasm pleasure such as decreased or absent pleasure.153e157 Such providers also manage women distressed with compromises in orgasm timing such as orgasms that occur spontaneously or too early. They manage women distressed with aversive J Sex Med 2016;13:1888e1906

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peripheral and/or central symptoms that occur before, during, or after orgasm and are not related to a compromise of orgasm quality.158e161 A broader, more diverse view of orgasm disorder in women would include orgasm disorders in which the primary orgasm complaint is a compromise of orgasm frequency, intensity, timing, and/or pleasure. Diagnostic Revision

Female orgasm disorders. FOD is characterized by a persistent or recurrent, distressing compromise of orgasm frequency, intensity, timing, and/or pleasure associated with sexual activity for a minimum of 6 months (Table 1).  Frequency: orgasm occurs with decreased frequency (decreased frequency of orgasm) or is absent (anorgasmia);  Intensity: orgasm occurs with decreased intensity (muted orgasm);  Timing: orgasm occurs too late (delayed orgasm) or too early (spontaneous or premature orgasm) than desired by the woman;  Pleasure: orgasm occurs with absent or decreased pleasure (anhedonic orgasm, PDOD). FOD can be classified as lifelong if the condition is present throughout the person’s life or acquired if the condition develops later in life. FOD can be classified as generalized if the condition is present at all times or situational if the condition is present only in certain situations. It is important to note that women demonstrate a wide variability of type and intensity of stimulation needed to reach orgasm. Many women require clitoral stimulation, and fewer women experience orgasm with vaginal penetration. FOD should not be diagnosed if a woman can achieve a clitoral orgasm but not vaginal penetration orgasm or has had inadequate stimulation.

Female orgasmic illness syndrome. FOIS is characterized by peripheral and/or central aversive symptoms that occur before, during, or after orgasm not related, per se, to a compromise of orgasm quality.158e161 Central aversive symptoms can include disorientation, confusion, impaired judgment, decreased verbal memory, anxiety, insomnia, depression (postcoital tristesse), seizures (orgasmic epilepsy), and/or headache (coital cephalalgia).161 Peripheral aversive symptoms can include diarrhea, constipation, muscle aches, abdominal pain, diaphoresis, chills, hot flashes, fatigue, akathisia, and genital pain. Such orgasm-associated symptoms can last for minutes, hours, or days after orgasm and can vary widely among women. As discussed earlier, the conditions of premature orgasm, PDOD, and FOIS are based on expert opinion. They should be considered provisional diagnoses until future research determines the validity of the diagnostic categories.

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Known Etiologies and Risk Factors The prevalence of the DSM-based classification of FOD (orgasm concerns plus distress) is 4.7%.162 Orgasmic problems are the second most frequently reported sexual problem in American women.163 There are no prevalence data on the current broader definition of orgasm disorders, including FOIS.

Female orgasmic disorder. FOD can be the result of insufficient central neurotransmitter or neuroendocrine or peripheral nervous system sexual excitatory processes or of increased central neurotransmitter or neuroendocrine sexual inhibitory processes.14,164 Sexual excitation and sexual inhibition imbalance resulting in FOD can be a consequence of psychosocial issues or psychological pathophysiologies.165 Organic pathophysiologic factors contributing to FOD include medications, medical problems, genital mutilation, complications from genital surgery or pelvic trauma, and hormonal issues. FOD also can be related to partner sexual dysfunctions (Table 6).130,132,134,154,164,166e168

Female orgasmic illness syndrome. Pathophysiologies associated with FOIS include psychological, musculoskeletal, autoimmune, vascular, and peripheral and/or central neurologic factors. A subcategory of FOIS can be an autoimmune disorder characterized by symptoms caused by orgasm-associated cytokine release.158e161

Strengths and limitations of orgasm consensus definitions. Strengths include the need for operationally functional definitions and the expansion of the existing nosology. Limitations include the lack of empiric evidence supporting the newly proposed nomenclature for FODs. More research is needed in the field of orgasm. More detailed knowledge of the female genital structures has found that there are many sites that, when stimulated together or alone, can be involved in the sexual arousal to orgasm.

CONCLUSION The consensus committee agreed on nomenclature and definitions for the desire, arousal, and orgasm domains of FSD, including disorders not designated in the DSM-5. This classification system will serve clinicians and researchers across disciplines for current and future patient management of women who request intervention for sexual dysfunction. It allows us to identify and label a full spectrum of sexual health problems, enabling specific diagnosis and use of currently available management strategies. This nomenclature provides a framework and the definitions will provide criteria for clinical trials of psychological, pharmacologic, and device therapies to be used by researchers and regulatory agencies. Areas of controversy that remain include validation of proposed diagnostic criteria, establishment of conventions for terminology, end points for evaluations of potential medications

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Table 6. Known etiologies and risk factors of female orgasmic disorders Insufficient central neuroendocrine or peripheral nervous system sexual excitatory processes Dopamine Oxytocin Melanocortin Norepinephrine Increased central neuroendocrine sexual inhibitory processes Opioid Endocannabinoid Serotonin Psychosocial issues Ineffective sexual communication or stimulation Traumatic relationship experience Mood disorder Fatigue Emotional concerns Past trauma, abuse history Cultural, religious prohibitions Feeling excess pressure to have a sexual experience Psychological pathophysiology Spectatoring (obsessive self-observation during sex) Unresolved marital conflict Religious guilt Fear of pregnancy Organic pathophysiologic factors Medications Selective serotonin reuptake inhibitor-induced sexual dysfunction Medical problems Diabetic neuropathy Multiple sclerosis Parkinson disease Spinal cord pathology Traumatic brain injury Genital mutilation Complications from Genital surgery Hysterectomy Pelvic trauma Hormone levels Low testosterone Low estrogen Low thyroid Increased prolactin Partner sexual dysfunctions Erectile dysfunction Premature ejaculation

and psychotherapeutic interventions, effects of the combination of medication and standardized psychotherapy in sexual desire disorders, usefulness of biologic measurements in diagnosis of sexual desire disorders, and under which category to place PGAD. Although the concept of arousal has been used J Sex Med 2016;13:1888e1906

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traditionally to refer to physical genital vasocongestion, arousal also has been used to refer to genital awareness. A clearer physiologic, conceptual distinction between these two processes is advisable, for example, in the case of “persistent genital arousal disorder,” in which genital awareness can occur in the absence of physical genital vasocongestion. The beta draft of the ICD-11 and preliminary reports from the ICD-11 committee implicate that a similar schema will be adopted as the basis for the new codes in the new category on “conditions related to sexual health.”169,170 Future directions for this nomenclature include research on its reliability and validity. Further research in pathophysiology and clinical presentations regarding PGAD, PDOD, and FOIS is needed to further refine these definitions. Further understanding regarding cultural differences, generational transitions, and the broad spectrum of sexual and gender preference norms are needed for these definitions to be successfully used by all users. Corresponding Author: Sharon J. Parish, MD, Weill Cornell Medical College, 21 Bloomingdale Road, White Plains, NY 10605, USA. Tel: 914-997-5207; Fax: 914-682-6943; E-mail: [email protected] Conflicts of Interest: Dr Parish is on the advisory board of or a consultant to Sprout, Emotional Brain, Palatin Technologies, and Pfizer Pharmaceuticals. Dr Andrew Goldstein is on the advisory board or a consultant to Emotional Brain and Strategic Sciences and Technology and has received grants or research funding from Palatin Technologies and Bayer. Ms Goldstein is on the advisory board of or a consultant to Lelo, Nuelle, Sprout, and SST and has received grants or research funding from Nuelle, Palatin, Shionogi, and TherapeuticsMD. Dr Irwin Goldstein is on the advisory board of or a consultant to Emotional Brain, Female Health Co, Nuelle, Shionogi, Sprout/ Valeant, and SST and received grants or research funding for “Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions—Part II.” Dr Pfaus is on the advisory board of or a consultant to Emotional Brain and Palatin Technologies and has received grants or research funding from the Canadian Institutes for Health Research and Natural Sciences and Engineering Research Council of Canada. Dr Clayton is on the advisory board of or a consultant to Lundbeck, Palatin Technologies, Pfizer, Inc, S1 Biopharmaceuticals, Sprout Pharmaceuticals, and Valeant Pharmaceuticals; has received grants or research funding from Auspex Pharmaceuticals, Forest Research Institute, Inc, Genomind, Inc, and Palatin Technologies; owns stock in Euthymics and S1 Biopharmaceuticals, Inc; and has received royalties from Ballantine Books, Random House, Changes in Sexual Functioning Questionnaire, and Guilford Press. Dr Giralidi is on the advisory board of or a consultant to Sandoz and Emotional Brain; is a speaker for Pfizer, Inc, and Eli Lilly; and is a stockholder of Novo Nordic. Dr Simon is on the advisory board of or a consultant to AbbVie, Inc, Amgen Inc, Apotex, Inc, Ascend Therapeutics, JDS Therapeutics, LLC, J Sex Med 2016;13:1888e1906

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Merck & Co, Inc, Noven Pharmaceuticals, Inc, Novo Nordisk, Nuelle, Inc, Perrigo Company, PLC, Radius Health, Inc, Regeneron Pharmaceuticals, Inc, Sanofi SA, Sermonix Pharmaceuticals, Inc, Shionogi Inc, Sprout Pharmaceuticals, Symbiotec Pharmalab, and TherapeuticsMD; has received grants or research funding from AbbVie, Inc, Actavis, PLC, Agile Therapeutics, Bayer Healthcare LLC, New England Research Institute, Inc, Novo Nordisk, Palatin Technologies, Symbio Research, Inc, and TherapeuticsMD; is a speaker for Amgen Inc, Eisai, Inc, Merck, Noven Pharmaceuticals, Inc, Novo Nordisk, and Shionogi Inc; and is a stockholder of Sermonix Pharmaceuticals. Dr Althof is on the advisory board of or a consultant to Allergan, Astellas, Aytu, Ixchelsius, Lilly, Promescent, Palatin, Sprout/Valeant, S1, and SST and has received grants or research funding from Allergan, Evidera, Ixchelsius, and Palatin. Dr Bachmann is on the advisory board of or a consultant to Edgewell Pharmaceutical; has received grants or research funding from Bayer; and received royalties from UpToDate. Dr Komisaruk is on the advisory board or a consultant to Nuelle and has received royalties from The Johns Hopkins University Press. Dr Levin is on the advisory board of or a consultant to Spectrum. Dr Spadt is on the advisory board of or a consultant to Lelo, Materna, Neogyn, and Nuelle and a speaker for Shionogi. Dr Kingsberg is on the advisory board of or a consultant to Sprout/Valeant, Pfizer, Novo Nordisk, Palatin, Nuelle, Materna, Emotional Brain, TherapeuticsMD, and SST and received stock dividends from Viveve. Dr Perelman has received remuneration from the MAP Education and Research Fund and Springer Publications. Dr Waldinger is on the advisory board of or a consultant to Emotional Brain BV. Dr Whipple reports no conflict of interest. Funding: None.

STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Sharon J. Parish; Andrew T. Goldstein; Sue W. Goldstein; Irwin Goldstein; James Pfaus; Anita H. Clayton; Annamaria Giraldi; James A. Simon; Stanley E. Althof; Gloria Bachmann; Barry Komisaruk; Roy Levin; Susan Kellogg Spadt; Sheryl A. Kingsberg; Michael A. Perelman; Marcel D. Waldinger; Beverly Whipple (b) Acquisition of Data Sharon J. Parish; Andrew T. Goldstein; Sue W. Goldstein; Irwin Goldstein; James Pfaus; Anita H. Clayton; Annamaria Giraldi; James A. Simon; Stanley E. Althof; Gloria Bachmann; Barry Komisaruk; Roy Levin; Susan Kellogg Spadt; Sheryl A. Kingsberg; Michael A. Perelman; Marcel D. Waldinger; Beverly Whipple (c) Analysis and Interpretation of Data Sharon J. Parish; Andrew T. Goldstein; Sue W. Goldstein; Irwin Goldstein; James Pfaus; Anita H. Clayton; Annamaria Giraldi; James A. Simon; Stanley E. Althof; Gloria Bachmann; Barry Komisaruk; Roy Levin; Susan Kellogg Spadt; Sheryl A. Kingsberg; Michael A. Perelman; Marcel D. Waldinger; Beverly Whipple

1902 Category 2 (a) Drafting the Article Sharon J. Parish; Andrew T. Goldstein; Sue W. Goldstein; Irwin Goldstein; James Pfaus; Anita H. Clayton; Annamaria Giraldi; James A. Simon; Stanley E. Althof; Gloria Bachmann; Barry Komisaruk; Roy Levin; Susan Kellogg Spadt; Sheryl A. Kingsberg; Michael A. Perelman; Marcel D. Waldinger; Beverly Whipple (b) Revising It for Intellectual Content Sharon J. Parish; Andrew T. Goldstein; Sue W. Goldstein; Irwin Goldstein; James Pfaus; Anita H. Clayton; Annamaria Giraldi; James A. Simon; Stanley E. Althof; Gloria Bachmann; Barry Komisaruk; Roy Levin; Susan Kellogg Spadt; Sheryl A. Kingsberg; Michael A. Perelman; Marcel D. Waldinger; Beverly Whipple Category 3 (a) Final Approval of the Completed Article Sharon J. Parish; Andrew T. Goldstein; Sue W. Goldstein; Irwin Goldstein; James Pfaus; Anita H. Clayton; Annamaria Giraldi; James A. Simon; Stanley E. Althof; Gloria Bachmann; Barry Komisaruk; Roy Levin; Susan Kellogg Spadt; Sheryl A. Kingsberg; Michael A. Perelman; Marcel D. Waldinger; Beverly Whipple

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