Symptom-associated alterations in functional connectivity in primary and secondary provoked vestibulodynia.

ABSTRACT: Primary provoked vestibulodynia (PVD) is marked by the onset of symptoms at first provoking vulvar contact, whereas secondary PVD refers to symptom onset after some period of painless vulvar contact. Different pathophysiological processes are believed to be involved in the development and maintenance of primary PVD and secondary PVD. The primary aim of this study was to test the hypotheses that the resting state functional connectivity of the brain and brain stem regions differs between these subtypes. Deep clinical phenotyping and resting state brain imaging were obtained in a large sample of a women with primary PVD (n = 46), those with secondary PVD (n = 68), and healthy control women (n = 94). The general linear model was used to test for differences in region-to-region resting state functional connectivity and psychosocial and symptom assessments. Direct statistical comparisons by onset type indicated that women with secondary PVD have increased dorsal attention-somatomotor network connectivity, whereas women with primary PVD predominantly show increased intrinsic resting state connectivity within the brain stem and the default mode network. Furthermore, compared with women with primary PVD, those with secondary PVD reported greater incidence of early life sexual abuse, greater pain catastrophizing, greater 24-hour symptom unpleasantness, and less sexual satisfaction. The findings suggest that women with secondary PVD show greater evidence for central amplification of sensory signals, whereas women with primary PVD have alterations in brain stem circuitry responsible for the processing and modulation of ascending and descending peripheral signals.

Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).

BACKGROUND: Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c. METHODS: Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. CONCLUSION: This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. ADMINISTRATIVE INFORMATION: Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.

Reduced concentrations of vaginal metabolites involved in steroid hormone biosynthesis are associated with increased vulvar vestibular pain and vaginal muscle tenderness in provoked vestibulodynia: An exploratory metabolomics study.

Provoked vestibulodynia (PVD) is a chronic vulvar pain disorder characterized by hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Knowledge regarding pathophysiological mechanisms contributing to the etiology and production of symptoms in PVD remains incomplete but is considered multifactorial. Using a cross-sectional observational study design, data from untargeted metabolomic profiling of vaginal fluid and plasma in women with PVD and healthy women was combined with pain testing and brain imaging in women with PVD to test the hypotheses that women with PVD compared to healthy women show differences in vaginal and plasma metabolites involved in steroid hormone biosynthesis. Steroid hormone metabolites showing group differences were correlated with vulvar vestibular pain and vaginal muscle tenderness and functional connectivity of brain regions involved in pain processing in women with PVD to provide insight into the functional mechanisms linked to the identified alterations. Sensitivity analyses were also performed to determine the impact of hormonal contraceptive use on the study findings. Women with PVD compared to healthy controls had significant reductions primarily in vaginal fluid concentrations of androgenic, pregnenolone and progestin metabolites involved in steroidogenesis, suggesting localized rather than systemic effects in vagina and vulvar vestibule. The observed reductions in androgenic metabolite levels showed large effect size associations with increased vulvar vestibular pain and vulvar muscle tenderness and decreases in androgenic and progestin metabolites were associated with decreased connectivity strength in primary sensorimotor cortices. Women with PVD showed symptom-associated reductions in vaginal fluid concentrations of metabolites involved in the biosynthesis of steroid hormones previously shown to affect the integrity of vulvar and vaginal tissue and nociceptive processing. Deficiency of certain steroids may be an important mechanism contributing to the pathophysiology of symptoms in PVD may provide potential diagnostic markers that could lead to new targets for therapeutic intervention.

Chronic Pelvic Pain in Women: A Review.

IMPORTANCE: Chronic pelvic pain (CPP) is a challenging condition that affects an estimated 26% of the world's female population. Chronic pelvic pain accounts for 40% of laparoscopies and 12% of hysterectomies in the US annually even though the origin of CPP is not gynecologic in 80% of patients. Both patients and clinicians are often frustrated by a perceived lack of treatments. This review summarizes the evaluation and management of CPP using recommendations from consensus guidelines to facilitate clinical evaluation, treatment, improved care, and more positive patient-clinician interactions. OBSERVATIONS: Chronic pelvic pain conditions often overlap with nonpelvic pain disorders (eg, fibromyalgia, migraines) and nonpain comorbidities (eg, sleep, mood, cognitive impairment) to contribute to pain severity and disability. Musculoskeletal pain and dysfunction are found in 50% to 90% of patients with CPP. Traumatic experiences and distress have important roles in pain modulation. Complete assessment of the biopsychosocial factors that contribute to CPP requires obtaining a thorough history, educating the patient about pain mechanisms, and extending visit times. Training in trauma-informed care and pelvic musculoskeletal examination are essential to reduce patient anxiety associated with the examination and to avoid missing the origin of myofascial pain. Recommended treatments are usually multimodal and require an interdisciplinary team of clinicians. A single-organ pathological examination should be avoided. Patient involvement, shared decision-making, functional goal setting, and a discussion of expectations for long-term care are important parts of the evaluation process. CONCLUSIONS AND RELEVANCE: Chronic pelvic pain is like other chronic pain syndromes in that biopsychosocial factors interact to contribute and influence pain. To manage this type of pain, clinicians must consider centrally mediated pain factors as well as pelvic and nonpelvic visceral and somatic structures that can generate or contribute to pain.

Dysregulation in Sphingolipid Signaling Pathways is Associated With Symptoms and Functional Connectivity of Pain Processing Brain Regions in Provoked Vestibulodynia.

Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention. PERSPECTIVE: This manuscript presents the results of a robust, unbiased molecular assessment of plasma and vaginal fluid samples in women with provoked vestibulodynia compared to healthy controls. The findings suggest that alterations in sphingolipid signaling pathways are associated with symptoms and brain biomarkers and may be an important molecular marker that could provide new targets for therapeutic intervention.

Striatal dopamine D2-type receptor availability and peripheral 17ß-estradiol.

Research using rodent models has established a relationship between the steroid hormone estrogen and dopamine function, by revealing changes throughout the estrous cycle and by directly manipulating neuroendocrine signaling through ovariectomy and administration of estrogen. However, a direct link between estrogen levels and dopamine signaling had not been established in humans. The goal of this study, therefore, was to assess the relationship between circulating 17ß-estradiol and dopamine signaling in the human brain by testing for a relationship between two proxies for these variables: peripheral 17ß-estradiol and striatal dopamine D2-type receptor availability, measured with [18F]fallypride and positron emission tomography (PET). Sixteen (23-45 years of age) women were tested on 2 days of the menstrual cycle estimated prospectively to occur during (a) the early follicular phase, when estrogen levels are near their nadir, and (b) the periovulatory phase, when estrogen levels peak. PET scans with [18F]fallypride were performed on these 2 days, and serum 17ß-estradiol was measured using radioimmunoassay. Dopamine D2-type receptor availability did not differ significantly in the whole striatum or the caudate, putamen, or accumbens subregions during the high-estrogen vs. the low-estrogen phases of the menstrual cycle. We conclude that circulating estrogen levels do not affect dopamine D2-type receptor availability in the human striatum although other indices of dopaminergic function may be affected.

Effects of oral contraceptive pills on mood and magnetic resonance imaging measures of prefrontal cortical thickness.

Gonadal hormones influence neuronal organization and plasticity. Yet the consequences of altering their concentrations by administering contraceptive agents, which are used by most reproductive-age women in the United States, are unclear. Cross-sectional studies have found both larger and smaller cortical regions alongside a variety of mood alterations in women who use oral contraceptive pills (OCPs) compared to naturally-cycling women. The goal of this study, therefore, was to determine whether there is an effect of OCPs on MRI measures of prefrontal cortical brain structure that may influence regulation of mood. We performed a double-blind, placebo-controlled, randomized crossover study comparing effects of OCPs (0.15 mg levonorgestrel + 0.30 µg ethinyl estradiol) vs placebo (N = 26) on MRI measures of prefrontal cortical thickness and on mood, as indicated by self-report on the Daily Record of Severity of Problems, which also includes one item related to somatic symptoms. MRI measures that reflect cortical thickness were smaller bilaterally in the pars triangularis and in the pars opercularis and frontal pole of the right hemisphere during the OCP arm vs. placebo. Only the effect in the right pars triangularis survived multiple comparisons correction. Right pars triangularis MRI measures of cortical thickness were not related to mood symptoms, but negatively correlated across conditions with severity of somatic symptoms on the DSRP. The somatic symptoms and MRI measures may be independently related to the actions of steroid hormones in OCPs, with OCPs simultaneously inducing both more effects on MRI measures of cortical thickness and somatic symptoms.

Predictors of Mucosal and Muscle Pain in Vulvodynia: A Cross-Sectional Analysis From the National Vulvodynia Registry.

Diagnostic criteria for provoked vestibulodynia (PVD) rely on mucosal pain in the vulvar vestibule, with less emphasis on pain from pelvic floor muscles. It is unknown how psychosocial variables associated with PVD are differentially associated with mucosal versus muscle pain. Analysis of data from the National Vulvodynia Registry (n = 202) revealed several factors associated with increased mucosal pain: pain duration (P = .043), the McGill sensory subscore (P = .0086) and the Gracely pain scale (P< .001). Increased mucosal pain was also associated with decreased arousal (P = .036). On the other hand, factors significantly associated with greater muscle pain included number of comorbid pain conditions (P = .001), decreased intercourse frequency post PVD onset (P = .02) and higher scores on the McGill sensory (P = .0001) and affective (P = .0002) subscores, the Gracely pain scale (P = .0012), and state anxiety (P < .001). Sexual function was also significantly impacted by high pelvic floor muscular pain, with lower scores for arousal (P = .046), orgasm (P = .0014) and satisfaction (P = .013), and higher pain (P = .01). Significant differences in the relationship between muscle and mucosal pain for pain duration (P = .005), McGill affective score (P = .001), orgasm (P = .049), change in intercourse frequency (P = .027), and state anxiety (P = .030) suggest the possibility of mucosal or muscle pain predominant PVD subtypes. PERSPECTIVE: Patients with higher pelvic floor muscle pain scores than mucosal pain scores may represent different subgroups or characteristics of patients with provoked vestibulodynia. This research highlights the importance of assessment of the pelvic floor muscles in addition to the cotton swab test of the vestibule.

Ecological Momentary Assessment of Non-Menstrual Pelvic Pain: Potential Pathways of Central Sensitization in Adolescents and Young Adults with and without Primary Dysmenorrhea.

PURPOSE: Primary dysmenorrhea (PD; menstrual pain without an identified organic cause) has been proposed as a possible risk factor for the development of chronic pelvic pain, but the mechanism through which this process occurs is unknown. One possible mechanism is central sensitization - alterations in the central nervous system that increase responsiveness to pain leading to hypersensitivity. Repeated episodes of pain, such as those experienced over time with PD, may alter how the brain processes pain. Ecological momentary assessment (EMA; collection of data in real time in participants' natural environments) is a novel data collection method that may help elucidate pain occurring during non-menstrual cycle phases. PATIENTS AND METHODS: The current observational study assessed the feasibility and acceptability of using EMA via text messages to collect pelvic pain data during menstrual and non-menstrual cycle phases in a community sample of adolescents and young adults (AYA) aged 16-24 years with and without PD and explored occurrence rates and intensity of non-menstrual pelvic pain (NMPP) in each of these groups. RESULTS: Thirty-nine AYA with PD and 53 healthy controls reported pelvic pain level via nightly text message. Global response rate was 98.5%, and all participants reported that the EMA protocol was acceptable. AYA with PD reported higher intensity (2.0 vs 1.6 on 0-10 numeric rating scale; p=0.003) and frequency (8.7% vs 3.1% of days; p=0.004) of NMPP compared to healthy controls. CONCLUSION: The EMA protocol was feasible and acceptable. Though both the intensity and frequency of NMPP were low and at levels that would not typically warrant clinical assessment or intervention, these repeated nociceptive events may represent a potential mechanism contributing to the transition from cyclical to chronic pelvic pain in some individuals.

Effectiveness of transdermal nicotine patch in premenopausal female smokers is moderated by within-subject severity of negative affect and physical symptoms.

RATIONALE: Nicotine patches may be less effective in female compared with male smokers. However, it is unknown if negative affect and physical symptoms influence transdermal nicotine patch-related effects on smoking behaviors. METHODS: Eighty-one acutely tobacco-abstinent premenopausal female smokers attended three counter-balanced experimental sessions across the menstrual cycle (early follicular, late follicular, and mid-luteal) and were randomized to patch condition (nicotine [21 mg] vs. placebo [0 mg] transdermal patch). Negative affect and physical symptoms were assessed prior to patch administration. The patch was removed 5 h post-administration, and participants completed a smoking reinstatement task. Multilevel linear models tested associations of patch condition, negative affect and physical symptoms, and their interaction on smoking behavior. RESULTS: There was a significant patch condition × Negative Affect and Pain symptoms interaction on the number of cigarettes smoked (p < 0.05). When Negative Affect and Pain were lower-than-usual, females administered a nicotine patch smoked significantly fewer cigarettes than females administered a placebo patch (p < .05), but there were no significant patch differences when Negative Affect and Pain were higher-than-usual. There was also a significant patch condition × Negative Affect interaction on time delay. The effects of patch condition on time delay to smoking were greater during sessions in which Negative Affect was higher-than-usual. CONCLUSIONS: Results suggest that among female smokers transdermal nicotine patch effectiveness may interact with negative affect and pain. Understanding and considering female-specific factors that may impact the efficacy of one of the most commonly used cessation medications is important for improving smoking cessation in female smokers.

Resting-state functional connectivity in women with PMDD.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is an understudied, debilitating disorder of women. Given evidence for prefrontal cortical and limbic dysfunction in PMDD, we compared intrinsic connectivity of the executive control network (ECN), default mode network (DMN), and amygdala in women with PMDD vs. controls. METHODS: Thirty-six women (18 PMDD, 18 control) participated in fMRI during the follicular and luteal phases of the menstrual cycle. At each time, resting-state functional connectivity was evaluated both before and after participants performed an emotion regulation task. The ECN was identified using independent components analysis, and connectivity of left and right amygdala seeds was also evaluated. RESULTS: Nonparametric permutation testing identified a cluster in the left middle temporal gyrus (MTG) with significantly stronger connectivity to the left ECN in women with PMDD vs. controls in all four fMRI sessions. Women with PMDD exhibited no difference in functional connectivity between menstrual cycle phases. Amygdala connectivity did not differ between the groups but differed significantly with menstrual phase, with left amygdala connectivity to cingulate cortex being significantly stronger during the follicular vs. luteal phase. Right amygdala connectivity to the middle frontal gyrus was also stronger during the follicular vs. luteal phase, with no group differences. These findings suggest that women with PMDD have different intrinsic network dynamics in the left executive control network compared to healthy controls.

Contraception counseling for women with premenstrual dysphoric disorder (PMDD): current perspectives.

Premenstrual Dysphoric Disorder (PMDD) is a severe form of premenstrual syndrome (PMS) affecting up to 7% of reproductive age women. Women with PMDD are of reproductive age; therefore, contraception and treatment of PMDD are important considerations. The disorder as described in the DSM-V is characterized by moderate to severe psychological, behavioral and physical symptoms beginning up to two weeks prior to menses, resolving soon after the onset of menstruation and significantly interfering with daily functioning. PMDD develops in predisposed individuals after they are exposed to progesterone at the time of ovulation. It has been hypothesized that PMDD is in part attributable to luteal phase abnormalities in serotonergic activity and to altered configuration of ℽ-aminobutyric acid subunit A (GABAA) receptors in the brain triggered by the exposure to the neuroactive steroid progesterone metabolite, allopregnanolone (Allo). A large body of evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can be effective in the treatment of PMDD. Combined hormonal contraceptive (CHC) pills, specifically the 20 mcg ethinyl estradiol/3mg drospirenone in a 24/4 extended cycle regimen has been shown to significantly improve the emotional and physical symptoms of PMDD. Other combined monophasic, extended cycle hormonal contraceptive pills with less androgenic progestins may also be helpful, although not well studied. Copper intrauterine devices (IUDs) are recommended for those not seeking hormonal contraceptives. Progestin-only methods including the progestin-only pill (POP), levonorgestrel (LNG) IUD, etonorgestrel implant or depot medroxyprogesterone acetate (DMPA) have the potential to negatively affect mood symptoms for women with or without baseline mood disorders, including PMDD. Careful counseling and close follow-up is recommended for patients with PMDD seeking these contraceptive methods.

Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vulvodynia: a voxel-based morphometry study.

Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study, we tested the hypotheses that PVD compared with healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD vs HCs. In addition, disease specificity of GMV alterations were examined by comparing PVD with another chronic pain disorder. Finally, we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, and 29 irritable bowel syndrome [IBS]). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared with HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to patients with IBS, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional GMV alterations were associated with patient reports of pain during intercourse and muscle tenderness. The current findings provide further evidence that GMV is increased in PVD compared with HCs in several regions of the sensorimotor network and the hippocampus in patients with PVD. In addition, GMV distinct alterations in the sensorimotor network were identified between 2 pelvic pain disorders, PVD compared with IBS.

Experimental evaluation of central pain processes in young women with primary dysmenorrhea.

Primary dysmenorrhea (PD; menstrual pain without an underlying medical condition) is associated with enhanced pain sensitivity and temporal summation (TS) in adult women, which may reflect the presence of central pain processes. Research in this area has been limited by focusing on only adult populations and incomplete assessments of central sensitization. The current study explored both excitatory and inhibitory measures of pain processing in girls and young adult women with and without PD. Thirty-two young women with PD and 34 healthy controls underwent laboratory pain testing during each of 3 menstrual cycle phases (menstrual, ovulatory, and midluteal), which included measures of pain tolerance and threshold, TS, and conditioned pain modulation. Results indicated enhanced pain sensitivity in young women with PD as measured by heat pain tolerance and Average Pain50 (P50), compared with healthy controls. These group differences were evident at all phases of the menstrual cycle. No group differences in cold pain tolerance, TS, or conditioned pain modulation were evident at any phase of the menstrual cycle. These data suggest some evidence of central sensitization in young women with PD, although no evidence of enhanced excitatory or deficient inhibitory mechanisms were observed. Future research should focus on identifying other potential phenotypes for PD to determine those at risk of developing other pain problems.

Patterns in Vulvodynia Treatments and 6-Month Outcomes for Women Enrolled in the National Vulvodynia Registry-An Exploratory Prospective Study.

BACKGROUND: Vulvodynia is a poorly characterized condition with multiple treatment options that have been described as largely ineffective in research settings. AIM: To describe treatment patterns in women enrolled in the National Vulvodynia Registry and determine if there is an association between selected treatments and patient-reported outcomes such as pain, sexual function, and psychological distress after 6 months of treatment. METHODS: Participants completed questionnaires on general medical history and patient-reported outcomes using the short-form McGill Pain Questionnaire, the Female Sexual Function Index, the Short Form-12 quality-of-life questionnaire, the Coping Strategies Questionnaire, and the State-Trait Anxiety Inventory. The evaluation also included pain sensitivity assessment of the vaginal mucosa using a cotton-tipped applicator and the vaginal muscles using a single-digit. In this prospective cohort study, all measurements were collected at baseline and again at 6 months after treatment. OUTCOMES: Type of treatment, number of treatments, self-reported pain intensity, dyspareunia, and pain-related psychological distress measures are reported at baseline and 6 months. RESULTS: Of 344 women enrolled, 282 received treatment; 78 different treatments were identified and categorized by type (eg, topical, oral, physical therapy) and number. The most commonly used treatments were topical (85%, n = 241), physical therapy (52%, n = 147), and oral medications (45%, n = 128). Notably, 73% of participants received ≥2 treatments. There was no association between type or number of treatments and patient characteristics. At 6 months, women reported improvements in general pain (P = .001), pain during intercourse (P = .001), catastrophizing (P = .000), and anxiety (P = .000). The Short Form-12 quality-of-life questionnaire showed improvements in physical limitations (P = .024), emotional limitations (P = .003), well-being (P = .025), and social function (P = .010). However, all domains of the Female Sexual Function Index indicated worsening in sexual function (P = .000) except for pain. CLINICAL TRANSLATION: Multi-modal treatments were most commonly used in clinical practice and improvements in patient-reported outcomes such as quality of life, distress, and pain were noted; however, participants who returned at 6 months continued to report poor sexual function. CONCLUSIONS: Strengths include a prospective and long-term study design that evaluated women in clinical settings. Limitations include a high rate of loss to follow-up for certain measures and inability to evaluate efficacy of individual treatments. In a setting where women were receiving highly specialized care, we found wide variation in the type and number of treatments used to treat vulvodynia. Despite this heterogeneity in treatment selection, women reported significant improvements in all study measures except sexual function. Lamvu G, Alappattu M, Witzeman K, et al. Patterns in Vulvodynia Treatments and 6-Month Outcomes for Women Enrolled in the National Vulvodynia Registry-An Exploratory Prospective Study. J Sex Med 2018;15:705-715.

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs. PERSPECTIVE: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system.

Rates of Anovulation in Adolescents and Young Adults with Moderate to Severe Primary Dysmenorrhea and Those without Primary Dysmenorrhea.

STUDY OBJECTIVE: To evaluate rates of presumptive anovulation in eumenorrheic adolescents and young adults with moderate to severe primary dysmenorrhea and those without primary dysmenorrhea. DESIGN: Participants completed luteinizing hormone surge ovulation predictor test kits. Anovulatory cycles were defined by never receiving a positive result before the next menstrual period; participants were grouped as anovulatory if they experienced at least 1 anovulatory cycle during study participation. Participants rated daily level of menstrual pain on a 0-10 numeric rating scale. SETTING: A university-based clinical research laboratory. PARTICIPANTS: Thirty-nine adolescents and young adults (ages 16-24) with primary dysmenorrhea and 52 age-matched control girls. INTERVENTIONS AND MAIN OUTCOME MEASURES: Rates of presumptive anovulation. RESULTS: One hundred sixty-eight cycles were monitored, 29.8% (N = 50) of which were anovulatory (37.1% [39/105] vs 17.5% [11/63] of cycles in control and dysmenorrhea groups, respectively). During study participation, control girls were significantly more likely to have had at least 1 anovulatory cycle than were girls with primary dysmenorrhea (44.2% [23/52] vs 17.9% [7/39] of participants, respectively; P < .01). Cycle length and number of bleeding days between ovulatory and anovulatory cycles were similar. The primary dysmenorrhea group's maximum menstrual pain ratings did not differ between ovulatory and anovulatory cycles (4.77 and 4.36, respectively; P > .05). CONCLUSION: Our data support previous findings of increased rates of ovulation in primary dysmenorrhea. However, menstruation after anovulatory cycles can be as painful as menstruation after ovulatory cycles. These data support the idea that regular menses do not necessarily indicate that a normal ovulatory cycle has occurred. Previous implications that ovulation is necessary for the development of substantial menstrual pain are incomplete.

Brain activation during emotion regulation in women with premenstrual dysphoric disorder.

BACKGROUND: Difficulties in regulating emotions are linked to the core symptoms of premenstrual dysphoric disorder (PMDD). We therefore investigated the neural substrates of emotion-regulation problems in women with PMDD. METHODS: On the basis of self-evaluations over 2 months on the Daily Record of Severity of Problems, eligible participants were assigned to two groups: PMDD and control (18 per group). Functional magnetic resonance imaging (fMRI) and a well-validated task were used to assess brain function during emotion regulation. Participants were tested twice, once during the follicular (asymptomatic) and once in the late luteal (symptomatic) phase of the menstrual cycle. RESULTS: Women with PMDD gave higher ratings of negative affect in the luteal phase than in the follicular phase, and compared with healthy control participants during the luteal phase. A region-of-interest fMRI analysis indicated that during the late luteal phase, women with PMDD had hypoactivation in right dorsolateral prefrontal cortex (dlPFC) during all conditions of the emotion-regulation task, not only in the contrast that isolated emotion regulation. An exploratory whole-brain, voxel-wise analysis showed that women with PMDD had less activation in the precentral gyrus during the luteal phase than the follicular phase, and less activation in the postcentral gyrus compared with control participants. CONCLUSIONS: During the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions. Hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD. Hypofunction in the right pre- and postcentral gyri warrants additional study.

Experimental and procedural pain responses in primary dysmenorrhea: a systematic review.

Primary dysmenorrhea (PD) has been the focus of a number of experimental pain studies. Although a number of reviews exist, few have critically evaluated the existing body of research on PD and experimental and procedural pain. Data from 19 published research articles that include women with PD and responses to an experimental or procedural pain stimulus (or stimuli) suggest that women with PD may have elevated pain reactivity, as compared to women without PD. This pattern appears to be true across different phases of the menstrual cycle. However, there is an abundance of conflicting findings, which may be due to significant methodological issues such as inconsistent definitions of PD, wide variation in experimental pain methodologies, and inaccurate assessment of the menstrual cycle. Future research should focus on identifying specific symptoms (i.e., pain threshold ratings) to more clearly define what constitutes PD, establish reliable and valid laboratory testing protocols, and assess the menstrual cycle with greater precision.