Persistent Genital Arousal Disorder: A Review of Its Conceptualizations, Potential Origins, Impact, and Treatment

Persistent Genital Arousal Disorder: A Review of Its Conceptualizations, Potential Origins, Impact, and Treatment Robyn A. Jackowich, BA,1 Leah Pink, MN, NP-Adult,2 Allan Gordon, MD,2 and Caroline F. Pukall, PhD1

ABSTRACT

Introduction: Persistent genital arousal disorder (PGAD) is a condition characterized by symptoms of physiologic (typically genital) sexual arousal in the absence of perceived subjective sexual arousal. The physiologic arousal can last hours or days, or it can occur constantly, and it does not typically remit after orgasm(s). The symptoms are usually described as distressing, intrusive, and unwanted. Aim: To review the available literature on PGAD. Methods: A literature review through April 2016 was undertaken using terms persistent genital arousal disorder, persistent sexual arousal syndrome, and restless genital syndrome. Main Outcome Measures: The main outcome is a review of the conceptualization of PGAD, its prevalence, proposed etiologies and treatments, and its impact on psychosocial and sexual functioning. Results: Much of the research on the potential etiologies and treatments of PGAD is published in the form of case studies. Several etiologies of PGAD have been proposed; however, a cause or causes have not been confirmed. A range of treatments has been explored primarily in case studies, from electroconvulsive therapy to oral medication, with variable success rates. Psychologically based treatments have been suggested but have yet to be evaluated. Online surveys have found initial evidence supporting the negative impact of PGAD on mental health and sexual functioning; however, more research is needed in this area. Conclusion: Although PGAD was first conceptualized 15 years ago, it remains a very under-researched condition. Currently, little is known about its biopsychosocial correlates, etiologies, or successful treatments. Future research directions are identified. Sex Med Rev 2016;-:1e14. Copyright
2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Key Words: Persistent Genital Arousal Disorder; Spontaneous Genital Arousal; Restless Genital Syndrome; Etiology; Conceptualization; Treatment

INTRODUCTION Persistent genital arousal disorder (PGAD) is a condition assumed to affect primarily women, although there have been three published case reports in men.1,2 It is characterized by symptoms of physiologic sexual arousal (genital vasocongestion, increased sensitivity of the genitals and nipples, etc) in the absence of feelings of subjective arousal.3,4 These symptoms are not fully relieved with any behavioral act or over-the-counter remedy, and they are described as intrusive, unwelcome, unpleasant, and sometimes painful. PGAD often results in great Received May 25, 2016. Accepted June 18, 2016. 1

Department of Psychology, Queen’s University, Kingston, ON, Canada;

2

Wasser Pain Management Centre, Mount Sinai Hospital, Toronto, ON, Canada

Copyright ª 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.sxmr.2016.06.003

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amounts of distress and is associated with feelings of shame, isolation, and suicidal ideation.3e6 PGAD was first described in the scientific literature by Leiblum and Nathan3 in a series of five case studies of women with varied experiences and diverse backgrounds. Leiblum and Nathan originally termed PGAD persistent sexual arousal syndrome based on a specific group of symptoms (see below). They later changed this label to PGAD to reflect the genital nature of the condition and to prevent confusion with persistent subjective sexual arousal or desire.6 Even with this change, PGAD is still confused with hypersexuality on a behavioral level7; women with PGAD and hypersexuality report a frequent and intrusive need for solitary or partnered sexual activity. Despite this behavioral similarity, hypersexuality is characterized by high subjective desire for sexual activity, whereas PGAD is typically characterized by high levels of genital arousal in the absence of desire. However, the differences between these two conditions have not been explored empirically. 1

2

Leiblum and Nathan3 originally proposed five criteria that represent PGAD: 1. Symptoms of physiologic sexual arousal (genital fullness or swelling and sensitivity with or without nipple fullness or swelling) that persist for hours or days and do not subside completely on their own; 2. These symptoms do not resolve with ordinary orgasmic experience and might require multiple orgasms over hours or days to remit (for some women, this might include spontaneous and intense orgasms different from deliberate orgasms resulting from sexual excitement and activity); 3. Symptoms of arousal are usually experienced as unrelated to any subjective sense of sexual excitement or desire; 4. The persistent genital arousal can be triggered not only by a sexual activity but also by non-sexual stimuli or by no apparent stimulus at all; 5. Arousal symptoms feel unbidden, intrusive, uninvited and unwanted, and the symptoms cause at least a moderate degree of distress. Leiblum and others have modified these features only slightly since the first description of PGAD, and sometimes distress is considered a separate, sixth criterion.6,8e10 Although Leiblum and Nathan are credited as being the first to label this condition and its presenting characteristics in 2001, descriptions of PGAD-like symptoms existed before 2001. Facelle et al,11 in a review of PGAD, described half a dozen historical cases, spanning from 200 AD to 1994. The paucity of research on PGAD before 2001 could indicate that a novel factor plays a role in its etiology; alternatively, individuals might have been reluctant to discuss these concerns for fear of stigmatization, or the collection of symptoms might have just gone unrecognized. These questions remain unanswered because a consensus has yet to be reached on the etiology of PGAD.

ETIOLOGY Although many etiologic hypotheses have been proposed, the cause or causes of PGAD remain unknown. It is likely not attributable to a single cause or biopsychosocial factor, and there may be subgroups of women within the PGAD group who develop the condition through a combination of factors. These hypothesized etiologies include central and peripheral dysregulation,5,12,13 vascular changes,14 meningeal cysts15,16 (most commonly Tarlov cysts), and pharmacologic,17 psychological,10 and dietary18 explanations. Little is known about the frequency or validity of each hypothesized etiology, because the majority of this work is in the form of individual case studies. A summary of the individual case studies related to potential etiologies is presented in Table 1.1,2,12,14,17e38 This summary includes the hypothesized etiology of PGAD, treatment modality undertaken, patient characteristics, and the investigators’ operationalization of

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treatment success. Assessments (physical, neurologic, cardiovascular, endocrine, etc) yielded no abnormal results in most cases; exceptions are described in the “symptom characteristics” column. Women with symptoms of persistent genital arousal have been asked about their own causal attributions of the symptoms. In an online survey of 103 women with PGAD conducted by Leiblum et al,39 participants indicated that sexual stimulation (n ¼ 51, 49.5%), masturbation (n ¼ 39, 37.9%), stress (n ¼ 35, 33.98%), and anxiety (n ¼ 30, 29.1%) were the most commonly reported activities associated with the original triggering of their symptoms. Although many instances of PGAD have no clear physical cause, some cases of PGAD have an identifiable morphologic etiology.15,16 Komisaruk and Lee16 requested that women in an online support group for PGAD submit sacral magnetic resonance (MR) images to determine the presence of Tarlov cysts, which form on dorsal (sensory) roots and have been found to result in genital dysesthesias or paresthesias (abnormal sensations). Of the 18 women who submitted their MR images, cysts were present in 12 (66.7%). A separate study identified 11 women with PGAD symptoms in a cohort of 1,045 patients with spinal meningeal cysts; Tarlov cysts were the most common type of meningeal cysts encountered in the PGAD group (n ¼ 8 of 11, 73%).15 Surgical treatment of these 11 women resulted in complete and lasting disappearance of symptoms in seven patients (64%) and significant improvement in symptoms in three (27%); only one (9%) reported no change in symptoms.15 These investigators believed that PGAD might be a previously undiscussed symptom of a compressed sacral nerve and noted that it is often present with other sacral radiculopathy symptoms, including pain (dyspareunia, sacral, perineal, and buttock pain) and bladder, bowel, and sexual dysfunction.15

PREVALENCE The exact prevalence of PGAD is not known. A survey of a sexual health clinic in the United Kingdom found that 1% (n ¼ 1 of 96) of women who agreed to participate in a brief questionnaire met all five of Leiblum and Nathan’s 2001 criteria for PGAD, and 33% (n ¼ 32 of 96) endorsed at least one criterion.40 A study of health care providers who address sexual health concerns indicated that 20% to 25% have patients with symptoms at least partly consistent with PGAD.5 Another source estimated the prevalence of PGAD to be 28% of women presenting with chronic pelvic pain.41 Because chronic pelvic pain affects 2.1% to 24.0% of all reproductive-age women,42 the prevalence rate for PGAD would range from approximately 0.5% to 6.7%. Women experiencing PGAD might be embarrassed to present to health care providers or fear being potentially misunderstood (eg, being mistakenly diagnosed with hypersexuality), thus contributing to an underestimation of prevalence. Lack of awareness by health care providers also can lead to underrecognition of PGAD and subsequent failure to make the Sex Med Rev 2016;-:1e14

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Persistent Genital Arousal Disorder: A Review

diagnosis. A series of three case studies gives an example of PGAD misdiagnosed as obsessive compulsive disorder in the context of Islamic religious bathing rituals.43 However, the number of women approaching health care providers about PGAD appears to be gradually increasing, perhaps owing to greater public and medical recognition of the condition.6,44 With greater recognition by the public, research, and clinical spheres, more attention is being given to potential conceptualizations of the disorder.

CONCEPTUALIZATIONS OF PGAD Restless Genital Syndrome Aquino et al30 and Waldinger et al35,45,46 hypothesized that symptoms of PGAD are part of a cluster of conditions that includes restless legs and/or overactive bladder syndrome. They believed PGAD could be attributable to small fiber neuropathy and is best referred to as “restless genital syndrome.” This conceptualization decreases the emphasis on sexual behavior, given that genital manipulation and orgasm do not resolve PGAD symptoms in most women.47 Viewing PGAD as restless genital syndrome focuses attention on the sensory rather than sexual characteristics of PGAD (similar to dysesthesias and/or paresthesias), much like the current conceptualization of vulvodynia in which the focus is on the pain characteristics.48,49 Waldinger et al36 also published case studies that support their conceptualization of PGAD, including a case of a woman whose symptoms did not resolve after a clitoridectomy; rather, the symptoms appeared to be due to neuropathy of the left pudendal nerve. Pink et al50 also noted two women who developed PGAD symptoms after damage to the pudendal nerve. Evidence for small fiber sensory neuropathy also was presented in a case study of two men who experienced symptoms of restless genital syndrome, drawing attention to the fact that PGAD is not exclusively experienced by women.2

Pain Component of Persistent Genital Arousal Some women with PGAD describe the intrusive feelings of genital arousal as painful, and as such, some have suggested that PGAD should be viewed as a subset of vulvodynia. An online survey conducted in women with PGAD found that 35% described their symptoms as painful. Of this group, 46% reported pain only with vaginal penetration, 29% reported pain without penetration, and 26% reported pain with and without penetration.39 In a follow-up study, Leiblum et al51 found that women who endorsed all five criteria of PGAD reported experiencing significantly more clitoral pain (n ¼ 42, 20.4%) and vaginal pain (n ¼ 36, 17.5%) than women who reported only some PGAD criteria (ie, <5). Women meeting all five criteria also reported significantly greater pain with penetration (mean ¼ 3.9, SD ¼ 2.3, P ¼ .03, where lower scores indicate greater pain) on the Female Sexual Function Index52 than women who reported only some of the criteria (mean ¼ 4.4, SD ¼ 2.1) and control women (mean ¼ 5.6, SD ¼ 1.1). Sex Med Rev 2016;-:1e14

Another study found that 83% of women described their vulvar sensations of PGAD in terms of words typically used to describe painful conditions, such as dysesthesia (abnormal sensations, eg, difficult to describe irritancies or sensations of imminent orgasm) and/or allodynia (painful sensations in response to a non-painful stimulus expressed as an inability to wear tight clothing).47 A number of women who presented to a chronic pain clinic for pelvic pain (n ¼ 9 of 15), urinary, bladder pain, interstitial cystitis-like symptoms (n ¼ 8 of 15), restless legs syndrome (n ¼ 5 of 15), and pudendal neuralgia (n ¼ 6 of 15) also endorsed PGAD symptoms.50 Noting the frequency with which women describe PGAD as painful, Markos and Dinsmore53 proposed a potential overlap between PGAD and vulvodynia and sought to compare the clinical features of these two conditions in a review of the two bodies of literature. They concluded that the two conditions were similar in their unknown etiologies, lack of observable biological abnormalities, psychological and medical comorbidities, exacerbation of symptoms with sleep, and individual responses to symptoms (eg, increased fear, hypervigilance, and catastrophizing). They argued that conceptualizing PGAD as a subtype of vulvodynia (ie, medically unexplained chronic vulvar pain) would aid in communication among clinicians, improve access of PGAD suffers to treatment (because some vulvodynia treatment options might benefit them if these conditions are indeed similar), and promote and unify evidence-based research efforts, which are currently lacking for PGAD. Women with PGAD also might find that viewing PGAD as a pain disorder would be more acceptable than viewing it as hypersexuality or a sexual dysfunction. A similar debate was held while leading up to the revisions to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition54 about whether dyspareunia (painful sexual intercourse, now genito-pelvic pain/penetration disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) was more appropriately considered a pain disorder rather than a sexual dysfunction (cf Binik48,55). A summary of studies that conducted an empirical evaluation of pain characteristics or provided descriptive statistics on painful PGAD symptom characteristics is presented in Table 2.39,46,50,51,56 Also of note, in 11 of the 28 articles presenting case studies reviewed in Table 1, patients described their PGAD symptoms as “painful.”

A Range of Responses to Persistent Arousal Symptoms Distress as a result of physiologic arousal symptoms is a key component in the diagnostic criteria for PGAD provided by Leiblium and Nathan.3 However, Leiblum and Chivers10 theorized that some women experience spontaneous sensations of genital arousal or persistent arousal symptoms that are not evaluated as distressing, but rather as pleasurable or only mildly distracting. Leiblum and Chivers10 proposed that it is the manner in which women relate to, or appraise, these arousal sensations that might contribute to the creation and maintenance of distressing persistent genital arousal symptoms. Anxiety about

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Table 1. Proposed etiologies and treatments for PGAD presented in case studies Proposed etiology

Patient characteristics

Symptom characteristics

Treatment

Increased soy intake (>4 lb/d)18

44-y-old woman, 5 children

5- to 6-mo duration of symptoms 5-y duration of symptoms; symptoms present most of the time, exacerbated by sleep/reclining; increased clitoral sensitivity Primary lifelong symptoms

Dietary modification and counseling Risperidone gradually increasing to dose of 2 mg/d over 4 wk

Central nervous system activation 66-y-old woman during sleep19

Hyperactive dopamine release20

49-y-old woman, bisexual, Caucasian, nulliparous

Venlafaxine (300 mg/d)21

32-y-old woman, married, bipolar, Symptoms started when she reached venlafaxine taking lithium, quetiapine (no 300 mg/d response), began venlafaxine 10 (of 15) women in online None support group 37-y-old single woman, 9-y duration of symptoms; heterosexual originally symptoms were constant, but over time became intermittent 52-y-old married woman, Symptoms intense and disabling good health for a couple of years, currently more infrequent and often relieved by multiple orgasms 46-y-old woman Symptoms lasted 3e4 wk after SSRI cessation 59-y-old single woman, Potential exacerbation of normal heterosexual return of sensation after discontinuation of SSRI 52-y-old woman, married 3-y duration of symptoms since with children she began taking lamotrigine for type II bipolar disorder

Discontinuation of SSRIs, unspecified22 Discontinuation of SNRIs, venlafaxine17

Discontinuation of SSRIs, sertraline17 Lamotrigine for type II bipolar disorder23

52-y-old woman, postmenopausal, 2 children, married

4-y duration of symptoms

Resolution of symptoms 3 consecutive nights of undisturbed sleep for the first time

Varenicline for smoking cessation Symptoms returned approximately 2 wk after initiation of (decreasing central dopamine varenicline release) venlafaxine decreased to Lower dose lead to resolution 150 mg/d of symptoms None

None

Escitalopram oxalate 1/4 tablet Decrease in number and intensity for situational anxiety and worry of orgasms during sex

None

None

Cessation of ssris

PGAD symptoms resolved 3e4 wk after SSRI cessation None

None

Symptoms (persistent genital Began with acute course of ect, arousal and depression then every 2 wk, plus low-dose symptoms) “completely gone” paroxetine (10 mg) and lowimmediately after treatment, but dose valproic acid; maintenance slowly returned over 2-wk ect eventually decreased to period until next ect treatment every 4e5 wk Symptoms completely subsided Acute course of 6 bilateral ECT immediately after ECT and treatments and then as needed slowly returned over 2-wk every 2 wk to 1 treatment per period year; low-dose paroxetine (10 mg) and low-dose valproic acid (250 mg) also prescribed (continued)

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Discontinuation of SSRIs, paroxetine (for type I bipolar disorder)20

Outcome measurements and success

Table 1. Continued

Beginning SSRIs, fluoxetine17 None26

Discontinuation of citalopram27

None28

None28

Patient characteristics 58-y-old woman with longstanding history of bipolar disorder and Tourette syndrome 29-y-old woman, heterosexual, no children 52-y-old woman, married

Symptom characteristics 1.5-y duration of symptoms

Treatment Acute course of ECT followed by weekly maintenance ECT

2-y duration of symptoms

None

Outcome measurements and success Initially asymptomatic after treatment, with symptoms returning after 1-wk period None

Decrease in patient’s anxiety and Couple therapy with cognitive urge to masturbate; also less behavioral treatment tension with partner, which was techniques, initially once per maintaining symptoms week for 18 mo, then at longer intervals; amitriptyline (10 or 20 mg) to help with sleep Symptoms resolved after 60-y-old woman, married None Alternative SSRIs attempted discontinuation of SSRIs (paroxetine, venlafaxine, sertraline, or escitalopram) w50 spontaneous orgasms 9 sessions of inhibitory TMS, 50 Decrease in depressive symptoms; 29-y-old woman, chronic pelvic daily sessions of cTBS over 3 mo striking decrease in pelvic pain pain due to interstitial cystitis, and PGAD (including lifelong anxiety, and depression spontaneous orgasms) with suicidal ideation; biopolar symptoms; remission of all disorder suspected symptoms (except PGAD) within 2 mo; managed well with additional treatments 8-wk history of symptoms Lorazepam 1 mg/d and duloxetine Symptoms improved over 2-wk 57-y-old woman, married, noninpatient admission; mood and 30 mg/d, with paroxetine smoker, and history of binge tapered off; group B b-hemolytic anxiety also improved; no PGAD drinking; comorbid depression symptoms at follow-up streptococcus, treated with and anxiety clarithromycin 500 mg/d Shortly after treatment, symptoms 23-y-old woman, married, 1 child Unwanted genital sensations and Dorsal nerve of clitoris blocked with botulinum toxin fully remitted; symptoms feelings of imminent orgasm returned after 8 mo but were without subjective arousal; bearable sensations in vagina, at labia, and especially around clitoris Dorsal nerve of clitoris blocked Symptoms fully remitted; 38-y-old woman, married, 1 child Unwanted genital sensations, with botulinum toxin maintained at 6-mo follow-up feelings of imminent orgasm; sensations in labium and clitoral regions 3-mo duration of symptoms

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Proposed etiology Discontinuation of paroxetine and lamotrigine (for bipolar disorder and Tourette syndrome)23 Beginning trazodone (symptoms began 1 mo after starting)24 None25

(continued)

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Table 1. Continued Proposed etiology Patient characteristics After increased dose of mirapex29 71-y-old woman, married, Parkinson disease

Symptom characteristics Treatment Hypnotherapy (9 biweekly 3-y duration of symptoms; sessions, 45 min each) cyclical pattern (highest during evenings, lowest during nights and mornings)

Association with Parkinson disease30

65-y-old woman, diagnosed with Parkinson disease at 60-y-old

None31

33-y-old woman with anxiety disorder

Restless genital symptoms for 3 y; symptoms only occurred during evenings and nights and triggered by sitting or lying down Symptoms began at 32 y old, after becoming pregnant; symptoms worsened at night and during menstruation

Hypermobility-type Ehlers-Danlos 25-y-old woman, no pregnancies syndrome32

Accidental viewing of pornography 54-y-old man, history of UTIs and anxiety associated with this and minor complication after event1 vasectomy (scrotum pain, treated)

Peri-clitoral mass (compression of 51-y-old woman, no pregnancies, dorsal nerve of clitoris)33 postmenopausal, Caucasian

18-mo duration of labia edema; PGAD symptoms (throbbing and pulsating) even when edema not present 2-y duration of symptoms; constant symptoms even without sexual stimuli; temporary relief with orgasm, but followed by anxiety that intensified symptoms 6-mo duration of symptoms; temporary relief from orgasm

Pramipexole 0.25 mg at night

Outcome measurements and success Anxiety before and after treatments (25% improvement), depression, sleep quality, intensity of symptoms at best and worst, marital interference, and quality of life; 97% decrease in intensity of symptoms at best, 0% for symptoms at worst; quality of life improved by 77% and marital interference decreased by 96% Improved symptoms within a few days; benefits lasted for 9 mo, until symptoms became resistant to increases in dose

Decreased genital sensitivity, no Topiramate 50 mg nightly (in urge to self-stimulate, addition to regimen of maintained 3 wk later; after a paroxetine 50 mg/d and few days without topiramate, clonazepam 1 mg nightly), dose symptoms returned eventually increased to 200 mg nightly Pelvic floor physiotherapy for PGAD symptoms significantly edema, sertraline for PGAD decreased symptoms Symptoms decrease in intensity, reported feeling “more in control”

Peri-clitoral mass surgically removed (papillary hidradenoma)

After removal, gradual and complete resolution of pain and PGAD symptoms over several weeks (continued)

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Diazepam (20 mg/d) and pregabalin (50 mg/d)

Table 1. Continued

Start of amitriptyline (30 mg) tricyclic antidepressant after death of close friend34

Small fiber sensory neuropathy2

Small fiber sensory neuropathy2

None35

Outcome measurements and Symptom characteristics Treatment success Duloxetine (30 mg titrated to 60 Within 1 wk night orgasms 4-y duration of symptoms; mg once daily in morning) disappeared and symptoms permanent symptoms of lowdecreased considerably; after 4 intensity thumping/stabbing in mo symptoms remitted clitoris; spontaneous orgasms completely experienced between once in 2 wk to 3 times/wk at night 41-y-old woman Symptoms persisted after Pregabalin (75 mg in morning, 100 Symptoms decreased considerably in 2 wk and only mildly present amitriptyline stopped mg in evening); psychodynamic psychotherapy to cope with loss preceding menstruation or during high psychological of friend and daily stress pressure; discontinuation of pregabalin, symptoms returned in 2 wk; psychotherapy contributed to decrease of symptoms TENS After 1 wk, symptoms decreased 74-y-old man, married, Symptoms began 7 mo after by 90%, with no overactive 3 children, radical prostatectomy; sensations of bladder complaints prostatectomy at 73 y old being on the edge of orgasm; symptoms worse when sitting and better when walking or lying down; sensations located above pubic bone and along penis or testes; symptoms of overactive bladder; ultrasound and MRI of pelvis visualized varicocele at inguinal canal bilaterally around spermatic cords TENS (previous drug treatments No disappearance of symptoms 38-y-old man, married, 2 children Spontaneous ejaculation since were not effective) with TENS 34 y old in absence of erection; small amount of bladder urgency; spontaneous ejaculations occurred 1e3 times/d accompanied by unpleasant genital sensations TENS (placed 2 cm medial to tuber 1e2 mo later, 90% decrease of Symptoms began at 56 y; 56-y-old woman, married, genital sensations, spontaneous ischiadicum); used TENS as 2 children; cardiac asthma since spontaneous orgasms and needed: 30 min of TENS plus 1.5 orgasm, restless leg, and “profuse female ejaculation”; 52 y of age, treated with h rest, 6 times/d, at intensity of overactive bladder sensations of imminent b-blocker; underwent 3.0 mA orgasms; urgency to void hysterectomy at 42 y for removal of a myoma

Patient characteristics 36-y-old woman

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Proposed etiology None34

(continued) 7

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Table 1. Continued Treatment

Outcome measurements and success

2 d after blockade of ganglion 61-y-old woman, divorced, stellatum by levobupivacaine 5 2 children, postmenopausal, dL for dystrophy of left wrist35 smoker (5 cigarettes/d)

TENS (placed bilaterally on pubic bone); used TENS as needed (1.4e3.2 mA)

1e2 mo later, 100% decrease of genital sensations and overactive bladder

None36

Clitoridectomy (removal of clitoris and cura); local injection of bupivacaine hydrochloride monohydrate 0.5% 1 dl

Spontaneous orgasms remitted, but genital sensations remained after clitoridectomy; injection led to complete remittance of symptoms for 72 h; all symptoms returned after 4 d

V-brace, prolonged standing avoided, daily pelvic floor exercises, swimming (for lower extremity circulation) and referral to discuss SSRIs

1 wk later, symptoms markedly resolved; patient attributed this to V-belt and did not use SSRIs; 10 and 14 wk later, complete resolution of symptoms

Antiepileptic drug (topiramate 300 mg/d)

No symptoms of PGAD at 3- and 6-mo follow-up, no functional hyper-connectivity on follow-up fMRI

Proposed etiology

Fourth pregnancy, potential entrapment of pudendal nerve37

Functional hyper-connectivity of epileptic focus12

Patient characteristics

Symptom characteristics

(continued)

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Symptoms started suddenly at 61 y; genital sensations of imminent orgasm associated with engorgement of clitoris and labia and increased vaginal lubrication; urgency to void Symptoms began at 72 y; 77-y-old woman, widowed at spontaneous orgasm (2e3 54 y, 2 children; underwent times/d) and unusual genital reconstructive surgery for sensations; symptoms prolapsed uterus at 34 y; aggravated during sitting, better 49 underwent appendectomy when walking; urgency to void; at 49 y; regular smoker, history brief previous episode of of bronchitis symptoms at 51 y; MRI of pelvis disclosed varices in anterior and posterior uterine wall and dilated left-side ovarian vein 27-y-old doctoral student, 27 wk Symptoms began at 18 wk of pregnant with fourth child pregnancy; edema of vulva and vulvar varicosities along left outer labium; pelvic floor assessment indicated multiple sites of muscle hypertonicity 40-y-old woman Constant symptoms since 39 y, associated with tachycardia and accompanied by genital pain and intermittent orgasm-like sensations with no trigger; fMRI found PGAD symptoms correlated with increased functional connectivity between different brain areas: LPIG (epileptic focus), left middle frontal gyrus, left inferior and superior temporal gyrus, and left inferior parietal lobe

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cTBS ¼ continuous q-burst stimulation; ECT ¼ electroconvulsive therapy; fMRI ¼ functional magnetic resonance imaging; FSFI ¼ Female Sexual Function Index; LPIG ¼ left posterior insular gyrus; MRI ¼ magnetic resonance imaging; PGAD ¼ persistent genital arousal disorder; SNRI ¼ serotonin-norepinephrine reuptake inhibitor; SSRI ¼ selective serotonin reuptake inhibitor; TENS ¼ transcutaneous electrical nerve stimulation; TMS ¼ transcranial magnetic stimulation; UTI ¼ urinary tract infection.

Temporary relief with amitriptyline but symptoms soon returned 57-y-old woman, hysterectomy plus unilateral oophorectomy at 32 y Beginning fludrocortisone (for hypotension and bradycardia)38

70% improvement in symptoms 6 wk after treatment

Coil embolization of dilated 5-mo history of symptoms, incompetent left ovarian partial temporary relief with vein orgasm; Doppler ultrasound showed pelvic varices; MRI showed varices in pelvis, vaginal wall, perineum, inguinal region, and anterior abdominal wall Various medications tried in 3-y duration of symptoms after sequence: diazepam, brief use of fludrocortisone gabapentin, carbamazepine, (stopped because it did not paroxetine, pregabalin and relieve hypotension) amitriptyline (50 mg) 62-y-old woman, postmenopausal, Caucasian, 4 pregnancies, 3 children Pelvic congestion syndrome14

Table 1. Continued

Treatment Symptom characteristics Patient characteristics Proposed etiology

Outcome measurements and success

Persistent Genital Arousal Disorder: A Review

unwanted spontaneous feelings of genital arousal can result in increased autonomic nervous system activity (specifically, increased genital arousal) and cognitive narrowing (increased attention on the genital sensations), creating a distressing feedback cycle. To explore differences between these two groups of women, Leiblum et al51,57 conducted two online studies comparing women who met all criteria for PGAD with women who endorsed only some of the criteria. They found that although women were similar demographically,51 the women who met all the PGAD criteria reported greater depression, anxiety, panic attacks, higher monitoring of physical sensations, and negative feelings about their genital sensations compared with those who endorsed a partial list of symptoms.51,57 In addition, women who met only some of the criteria were significantly more likely to report positive evaluations of their feelings of persistent genital arousal, such as feeling pleased, happy, or sexy. Conversely, women who endorsed all the criteria were more likely to report continuous (vs intermittent) PGAD symptoms, significantly higher distress scores, and depressive and anxiety symptoms before the onset of their PGAD.51 Another consideration that has not yet received much research attention is the role of sexual abuse in the perception and expression of PGAD symptoms. Leiblum et al57 found that 52.6% (n ¼ 40) and 35.5% (n ¼ 27) of women reported a history of childhood sexual abuse and adult sexual victimization, respectively. Similarly, in the study by Pink et al,50 46.7% (n ¼ 7) reported a history of sexual abuse. Leiblum et al57 found that 11.8% (n ¼ 9) of women reported that they believed that sexual trauma contributed to their PGAD. Sexual abuse might increase the risk of PGAD, as has been demonstrated in other conditions affecting the genito-pelvic region (eg, vulvodynia,58 interstitial cystitis or painful bladder syndrome59).

PSYCHOLOGICAL IMPACT Women with PGAD report substantial personal cost in mental health (sometimes to the point of suicidal ideation or completion as highlighted in some media reports), sexual functioning, and ability to complete daily activities.5 What research exists in the psychosocial realm of PGAD focuses on general health correlates and sexuality; the mental health literature is sparse. A descriptive study of 103 women with PGAD concluded that although most women were in good overall physical health, distress about the condition was rated as moderate or high by 75% of respondents.39 The strongest predictors of distress included the intrusive and unwanted feelings of genital arousal; continuous symptoms; feelings of unhappiness, shame, and worry; and decreased sexual satisfaction. They also found that many women with PGAD self-reported high levels of worry (61.8%), stress (67.7%), and depression (42.7%).39 In a study that used a validated measurement of general psychological function, Carvalho et al41 conducted an online study

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Table 2. Pain characteristics Patient characteristics

Assessment of pain

Pain outcomes

Online survey of 103 women; 85% met 1 criterion for PSAS and 53% met all 5 criteria39

Self-report description of PSAS symptoms

Online survey of 388 women; 206 endorsed all 5 criteria of PGAD (“PGAD group”), whereas 176 endorsed some but not all criteria (“non-PGAD group”)52

Self-reported PGAD symptoms and responses to FSFI52

Online survey of 172 women, all of whom endorsed all 5 PGAD criteria56

Self-reported responses FSFI52

15 women with PGAD presenting at a pelvic and genital pain management clinic51

Interview and chart review of clinic files

23 women who met all 5 PGAD criteria presenting at an outpatient department of neurosexology46

In-depth interviews with all participants

Pain in clitoral and vaginal areas reported by 35.4% of women; pain with penetration reported by 45.7%, pain without penetration reported by 28.6%, and pain with and without penetration reported by 25.7%; 45.9% of women described the process of reaching orgasm as painful or physically distressing Significantly more women in PGAD group reported clitoral pain (20.4%, n ¼ 42) and vaginal pain (17.5%, n ¼ 36) than in nonPGAD group (clitoral 13.1%, n ¼ 23; vaginal 12.5%, n ¼ 22); PGAD group also reported significantly more pain on FSFI pain subscale (mean ¼ 3.8, SD ¼ 2.3) than non-PGAD group (mean ¼ 4.4, SD ¼ 2.1; lower scores indicate greater pain symptoms); normal controls (no PGAD symptoms; scores for healthy controls derived from previous publications are much higher (mean ¼ 5.6, SD ¼ 1.1) Compared with previously published literature, women who reported all 5 PGAD symptoms reported greater pain (mean ¼ 4.5, SD ¼ 1.9) than healthy controls (mean ¼ 5.6, SD ¼ 1.1) but less pain than women with female sexual arousal disorder (mean ¼ 4.0, SD ¼ 1.9); lower scores indicate greater pain symptoms 60% (n ¼ 9) reported comorbid pelvic and/or genital pain, 53.3% (n ¼ 8) reported bladderrelated pain, 20% (n ¼ 3) reported clitoral pain, and another 20% (n ¼ 3) reported neuropathic pain; PGAD symptoms described as burning (20%, n ¼ 3), associated with allodynia (46.7%, n ¼ 7), back pain (20%, n ¼ 3), abdominal pain (13.3%, n ¼ 2), and breast pain (6.7%, n ¼ 1); hyperalgesia noted in 33.3% (n ¼ 5) Of all women, 19 (83%) reported allodynia such that wearing tight clothing was not tolerable and provoked unwanted and difficult-todescribe genital symptoms and irritancies

FSFI ¼ Female Sexual Function Index; PGAD ¼ persistent genital arousal disorder; PSAS ¼ persistent sexual arousal syndrom.

of women with PGAD investigating psychosocial functioning, personality characteristics, and cognitive styles. To assess general psychological function in women with PGAD, they used the Brief Symptom Inventory—a 53-item self-report measurement used for assessing general psychological adjustment on nine dimensions, including depression, anxiety, and interpersonal sensitivity. Results indicated that women with PGAD fared significantly worse than non-affected women on all dimensions, except interpersonal sensitivity. However, the groups differed significantly on several important demographic variables (ie, age, marital status, years of education), which could confound the interpretation of these results.

In a second study, Carvalho et al60 found that (high) neuroticism, (low) openness, (high) sexual conservatism, and (low) dyadic adjustment significantly predicted PGAD-associated distress. They emphasized sexual conservatism as the most important factor related to distress, because it moderated the relationship between symptom severity and distress associated with those symptoms. Based on these results, Carvalho et al41,60 speculated whether there might a specific cognitive style that is common among women who experience PGAD. Carvalho et al make a strong point that if the predictors of distress associated with PGAD can be clearly identified, treatment options targeting the distress and its associated predictors will improve treatment Sex Med Rev 2016;-:1e14

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Persistent Genital Arousal Disorder: A Review

effectiveness. What is unclear from the results of Carvalho et al is the direction of the findings, for example, whether high sexual conservatism and/or low dyadic adjustment are predictive of PGAD or result from PGAD. The impact of and the relationship between PGAD and sexual attitudes need to be examined in more detail to understand these results.

SEXUAL FUNCTIONING Little is known about the impact of PGAD on sexual functioning. In Leiblum et al’s51 online study comparing women who endorsed all five PGAD symptoms with those who only endorsed some, those who endorsed experiencing all symptoms reported lower desire, less sexual satisfaction, greater pain, and lower overall scores on the Female Sexual Function Index.52 Another study by Leiblum and Seehuus56 found that women who met all five criteria of PGAD self-reported Female Sexual Function Index scores that were between published scores of healthy control women and those with female sexual arousal disorder on all areas, except sexual desire. On the desire subscale, women with PGAD scored significantly higher (indicating higher desire) than the female sexual arousal disorder group, but similarly to the control women. This sample eliminated all single women and women who self-identified as lesbian or bisexual; thus, these results might not be generalizable to a more diverse sample. In addition, although women with PGAD might appear to be functioning relatively well on a self-report measurement largely targeting physiologic response (arousal, lubrication, orgasm, etc), we require more information about the level of distress associated with these symptoms to determine a comprehensive picture of the impact of PGAD on sexuality.

TREATMENTS FOR PGAD Because the causes of PGAD have yet to be identified, a standardized treatment algorithm for PGAD has not been created. Some case studies have reported success with treatments such as electroconvulsive therapy,20,23 pelvic floor physiotherapy,37 hypnotherapy,29 botulinum toxin injections,28 transcutaneous electrical nerve stimulation,35 and various oral medications.12,34,46 The use of psychologically based interventions also has been recommended (including cognitive behavioral therapy and mindfulness-based therapies) to treat the impact of PGAD on psychological and sexual well-being.11,61 However, except for a single case study of couple therapy using cognitive behavioral techniques,25 this treatment option has yet to be empirically evaluated, likely because so little is known about the psychosocial correlates of PGAD.

CLINICAL IMPLICATIONS Although the prevalence of PGAD is suspected to be low, it is likely under-diagnosed and under-recognized. Clinicians in primary care, obstetrics and gynecology, urogynecology, and Sex Med Rev 2016;-:1e14

chronic pain management should ask about the presence of persistent arousal symptoms as a component of a comprehensive sexual and reproductive history. Asking about persistent arousal symptoms would be even more relevant in the context of a patient presenting with some of the characteristics and symptomology implicated in the etiology of PGAD, such as genitopelvic pain, bladder symptoms, Tarlov cysts, pelvic congestion, pelvic varices, pudendal neuralgia, and restless legs syndrome.50 If the patient meets the criteria for PGAD discussed in the literature, further inquiry should include history of sexual abuse, dietary factors (ie, increased soy intake), initiation or discontinuation of medications that coincided with symptom onset (ie, antidepressants or dopaminergic medications), and comorbid conditions such as Parkinson disease, Ehlers-Danlos syndrome, small fiber neuropathy, and pudendal nerve injury, entrapment, or lesion. If PGAD is being considered, then it is important to rule out differential diagnoses such as female priapism.62 Physical examination of patients with suspected PGAD should include examination of the external genitalia and sensory testing of the vulva and introital opening of the vagina.62 Investigations to consider would be a hormone panel,11 MR imaging of the pelvis to identify Tarlov cysts, MR neurography (if pudendal neuropathy is suspected), and MR venography to rule out pelvic varices or pelvic congestion.62 If possible, referral to a specialist familiar with PGAD for ongoing care would be beneficial. Although there is no standard approach to treating PGAD, possible treatments would be aimed at the reversal of any identifiable cause, which further highlights the significance of a thorough history, physical examination, and investigation. An important clinical implication to bear in mind is that PGAD patients might have unsuccessfully attempted to discuss their persistent genital arousal symptoms with health care providers in the past. This disclosure is an opportunity to acknowledge and validate symptoms that have been distressing and often disabling.

CONCLUSIONS AND FUTURE RESEARCH DIRECTIONS Research on PGAD is still in its infancy and is characterized by a large number of case studies, despite 15 years of investigation since the original findings by Leiblum and Nathan.3 Although some great advances have been made in identifying morphologic causes responsible for some cases of PGAD,15,16 many cases do not appear to have an identifiable physical cause. Many questions about the etiology, treatment, and impact of PGAD remain unanswered. Efforts have been undertaken to conceptualize the condition. It has been proposed that PGAD might be (i) part of a cluster of conditions related to small fiber neuropathy (restless genital syndrome), (ii) a subtype of vulvar pain,53 and/or (iii) problematic appraisal of spontaneous genital sensations.10 Further work to conceptualize PGAD and to confirm the complex symptom presentation could help guide future research and

12

treatment efforts. This process could start with a thorough clinical assessment, which would inform research avenues (eg, to confirm common symptom characteristics and potential PGAD subgroups, to explore the relationship between PGAD and other genito-pelvic pain conditions) and vice versa. In addition, it is clear that we need to continue expanding our knowledge of psychological, sexual, and social correlates of PGAD. Although there has been some success of treatment for individuals with PGAD as presented in various case studies, largescale treatment evaluations are needed. Due to the rarity of PGAD, this might require large-scale clinical trials that require national and/or international collaborations. Future assessment of treatment options also should include the evaluation of psychologically based treatments for PGAD that specifically target the psychosocial, sexual, and relationship difficulties that women with PGAD experience. With growing public and medical awareness, more individuals with PGAD are coming forward; however, many might still feel embarrassed about their symptoms or fear being misunderstood by their health care providers. A better understanding of the health care experiences of women with PGAD will shed light on the barriers to receiving care. Corresponding Author: Caroline F. Pukall, PhD, Department of Psychology, Queen’s University, Kingston, ON K7L 3N6, Canada. Tel: 613-533-3200; E-mail: [email protected] Conflicts of Interest: The Wasser Pain Management Centre has received educational support from Purdue Pharma and Allergan. Funding: None.

STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Robyn A. Jackowich; Caroline F. Pukall (b) Acquisition of Data N/A (c) Analysis and Interpretation of Data N/A Category 2 (a) Drafting the Article Robyn A. Jackowich; Caroline F. Pukall (b) Revising It for Intellectual Content Robyn A. Jackowich; Leah Pink; Allan Gordon; Caroline F. Pukall Category 3 (a) Final Approval of the Completed Article Robyn A. Jackowich; Leah Pink; Allan Gordon; Caroline F. Pukall

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