Exploring Localized Provoked Vulvodynia: Insights from Animal Model Research.

Provoked vulvodynia represents a challenging chronic pain condition, characterized by its multifactorial origins. The inherent complexities of human-based studies have necessitated the use of animal models to enrich our understanding of vulvodynia's pathophysiology. This review aims to provide an exhaustive examination of the various animal models employed in this research domain. A comprehensive search was conducted on PubMed, utilizing keywords such as "vulvodynia", "chronic vulvar pain", "vulvodynia induction", and "animal models of vulvodynia" to identify pertinent studies. The search yielded three primary animal models for vulvodynia: inflammation-induced, allergy-induced, and hormone-induced. Additionally, six agents capable of triggering the condition through diverse pathways were identified, including factors contributing to hyperinnervation, mast cell proliferation, involvement of other immune cells, inflammatory cytokines, and neurotransmitters. This review systematically outlines the various animal models developed to study the pathogenesis of provoked vulvodynia. Understanding these models is crucial for the exploration of preventative measures, the development of novel treatments, and the overall advancement of research within the field.

Immune Dysregulation, Inflammation in Characterizing Women with Vulvodynia, Depression, and Both.

Background: Depression and vulvodynia are often comorbid. The onset of depression and vulvodynia may be immune and/or stress/environmentally induced. We explored whether vulvodynia, depression, or both occur in response to a Th1-mediated versus Th2-mediated immune response. Materials and Methods: We analyzed data from a case-control study of clinically confirmed vulvodynia and history of depression determined through structured clinical interviews. Immune dysregulation and inflammation were categorized based on the following self-reported conditions: rheumatoid arthritis, Sjogren's disease, scleroderma, systemic lupus erythematosus, inflammatory bowel disease, fibromyalgia, osteoarthritis, polycystic ovarian syndrome, diabetes mellitus, uterine fibroids, asthma, atopic dermatitis, and allergic rhinitis. Logistic regression analyses were adjusted for marital status, body mass index, age, and pack years. Results: Women with systemic immune dysregulation had higher odds of depression (adjusted odds ratio [aOR] = 1.61, confidence interval [95% CI]: 0.65-3.98), vulvodynia (aOR = 2.45, 95% CI: 1.00-5.96), and comorbid depression and vulvodynia (aOR = 4.93, 95% CI: 2.19-11.10) versus neither condition. Women reporting local immune dysregulation had similar odds of depression (aOR = 1.89, 95% CI: 0.99-3.59), vulvodynia (aOR = 2.12, 95% CI: 1.08-4.18), and comorbid depression and vulvodynia (aOR = 1.96, 95% CI: 0.98-3.90). Women with Th2 inflammation had similar odds of depression (aOR = 2.23, 95% CI: 1.05-4.77) and vulvodynia (aOR = 2.56, 95% CI: 1.20-5.49). Women with Th1 or Th2 inflammation had similar odds of comorbid depression and vulvodynia (aOR = 3.03, 95% CI: 1.48-6.19; aOR = 3.14, 95% CI: 1.49-6.60, respectively). Conclusions: Our results suggest that an imbalance of cytokines, indicated by the presence of one or more immune-related health conditions, is associated with an increased risk of vulvodynia and/or depression.

Vulvodynia: A practical guide in treatment strategies.

Vulvodynia is a debilitating condition characterized by chronic vulvar pain, with a detrimental impact on the patient's overall quality of life. Its etiology is multifactorial, but still in the process of being clearly outlined. Vulvodynia is not a single entity. It is a heterogeneous condition characterized by multiple triggers, making it challenging to define a reference standard for its treatment. In this manuscript we selected all articles including the following key criteria: "vulvodynia". The primary outcomes observed included the resolution of chronic pelvic pain, dyspareunia and sexual satisfaction, psychological well-being, and overall quality of life. Most pharmacologic treatments require further evidence to be recommended. On the other hand, non-pharmacologic approaches such as psychotherapy, physical therapy, and surgery have received stronger support. This review summarizes pros and cons of adopting available treatments. Multimodal approaches should be introduced to improve patient outcomes. Further investigations are warranted to improve patients' quality of life.

Innervation of the human vulvar vestibule: A comprehensive review.

Pain of the vulvar vestibule, including provoked vestibulodynia, is prevalent among women, yet challenging to treat due to its multifactorial etiology. Recent evidence indicates a neuroproliferative subtype in which hypersensitivity of the vulvar vestibule is due, in part, to hyperinnervation. Detailed knowledge regarding the innervation of the vulvar vestibule is crucial to understanding and treating pain conditions impacting this region. The purpose of this review is to consolidate the current evidence regarding the innervation of the human vulvar vestibule and discuss the implications of this innervation for pathological conditions affecting this tissue. A comprehensive review of the literature was conducted using keywords including vulvar vestibule, innervation, and vestibulodynia to identify articles concerning the innervation of the vulvar vestibule. Fifteen studies published between 1998 and 2017 were reviewed. Evidence from immunohistochemical investigations support that the vulvar vestibule has nociceptive, mechanosensory, sympathetic, and parasympathetic innervation. In pathological samples, hyperinnervation supports the neuroproliferative etiology of provoked vestibulodynia. Additionally, there is some evidence supporting the role of the pudendal nerve in vulvar vestibule innervation, although no cadaveric studies have been reported to date. Progress has been made in our understanding of the innervation of the vulvar vestibule, though further research into the origin of sensory and autonomic innervation of this region is needed. Advancing the knowledge of vulvar vestibule innervation is crucial towards improving our understanding of the function of this tissue, in addition to informing the etiology and management of pain syndromes impacting this region.

Changes in the Vaginal Microbiota of Women With Secondary Localized Provoked Vulvodynia.

OBJECTIVE: The etiology of localized provoked vulvodynia (LPV) remains unknown, but observations suggest the involvement of the vaginal microbiota. We examined the vaginal microbiota of women with LPV and healthy controls, upon after a low-oxalate diet (LOD). MATERIALS AND METHODS: A total of 9 women diagnosed with secondary LPV and 21 healthy controls were recruited from the Galilee Medical Center in Israel and subjected to prospective evaluations of their vaginal microbiota. Total DNA was extracted from vaginal discharge samples provided before and after following LOD for 3 weeks and was then subjected to 16S sequencing. Data obtained were then used to evaluate α and ß diversity, identify differentially abundant bacterial taxa in LPV, and determine their impact on the metabolism. RESULTS: These evaluations revealed decreased diversity in the vaginal microbiota of women with LPV and identified the Ochrobactrum genus and Pseudomonadaceae family as indicators for LPV. In addition, we identified 23 differentially expressed bacterial metabolic pathways between the LPV and control samples and revealed that LOD could induce changes in the ß diversity of LPV vaginal microbiomes, which was further supported by some degree of pain reduction in patients. CONCLUSIONS: Localized provoked vulvodynia and LOD were associated with shifts in the vaginal microbiota. However, the impact of these changes on the development of LPV requires additional studies with a larger cohort.

Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors.

This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.

Surgical Treatments of Chronic Vulvar Pain After Female Genital Mutilation/Cutting.

BACKGROUND: Vulvar and in particular clitoral pain can affect women with Female Genital Mutilation/Cutting (FGM/C). To date, there is no comprehensive study on the different available treatments for vulvar pain after FGM/C. AIM: To study the outcome of surgical treatments of vulvar and/or clitoral pain among women living with FGM/C. METHODS: Retrospective review of the consecutive medical files of all 506 women who consulted at a specialized outpatient clinic for women with FGM/C between April 1, 2010 and December 31, 2017. OUTCOME: Subjective change in chronic vulvar pain after surgical treatment. RESULTS: In total, 36.1% of women (n = 183) experienced chronic pain, all types included, among which 2.8% (n = 14) experienced provoked or unprovoked chronic vulvar pain. Among the 14 women with provoked or unprovoked chronic vulvar pain, ten (71.4%) underwent surgical treatment: 7 underwent resection of vulvar scar complications (cysts, bridles, adhesions) with (n = 4) or without (n = 3) concomitant defibulation, 3 had clitoral reconstruction and one had labium reconstruction with removal of peri-clitoral adhesion. Nine out of ten (90%) experienced resolution of pain after surgery and the remaining woman (10%) was lost to follow-up. CLINICAL IMPLICATIONS: Safe and effective surgical treatments exist and patients with chronic vulvar pain post-FGM/C should be referred to specialists who would consider appropriate indications for surgery and support informed decision-making and treatment. STRENGTHS & LIMITATIONS: The strengths of this research are the big sample size of women from diverse cultural and religious backgrounds, as well as the availability of pre- and postsurgery iconographic material and histology. Limitations include a subjective reporting of pain without validated questionnaires. CONCLUSION: Effective surgical treatments for provoked or unprovoked chronic vulvar pain post-FGM/C are clitoral reconstruction, defibulation, cystectomy, and bridle removal. Surgical treatments should be combined with a culturally sensitive multidisciplinary care and follow-up. Bazzoun Y., Aerts L., Abdulcadir J. Surgical Treatments of Chronic Vulvar Pain After Female Genital Mutilation/Cutting. J Sex Med 2022;19:290-301.

[Multidisciplinary examination and treatment of vulvodynia].

Women suffering from chronic vulvar pain seek help in the healthcare system on numerous occasions. The most common type is provoked localized vulvodynia (PVD) in which the pain has been persistent for more than three months without identifiable cause. The aetiology of PVD is multifactorial and the diagnosis is based upon medical history and gynaecological assessment including a bio-psycho-social evaluation. Danish and international guidelines point to the advantages of a multidisciplinary approach, where physical, psycho-sexual assessment is integrated in a multidisciplinary treatment programme as summarized in this review.

Vulvodynia - an evolving disease.

Vulvodynia is a common vulval pain syndrome that occurs most commonly in reproductive women of all ages. It can, in some cases, present for the first time after menopause. Up to about 15% of adult women have had symptoms of vulvodynia, with 4-5% currently symptomatic. Since there are no specific tests for diagnosis, vulvodynia is a diagnosis of exclusion. The condition is commonly associated with other chronic pain disorders and can be exceedingly debilitating, resulting in sexual dysfunction, severe depression and/or anxiety. It can significantly impair quality of life. Goals for long-term team approach management should be discussed with the patient at the commencement of each intervention as effectiveness of therapy is not assured. Currently, there is no intervention that effects cure in all individuals and a combination of pharmacological therapy, psychotherapy and physiotherapy, reserving surgery as a last-line option, is the best option for treatment. There are no long-term data on how long women will have symptoms and, if resolved, what provokes symptoms again in the future, whilst correlation between the etiology of vulvodynia and efficacy of treatment is not known.

High rate of dyspareunia and probable vulvodynia in Ehlers-Danlos syndromes and hypermobility spectrum disorders: An online survey.

Vulvodynia is debilitating vulvar pain accompanied by dyspareunia (pain with sexual intercourse). Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) may represent a predisposing factor for vulvodynia given a high rate of dyspareunia in these conditions. We conducted an online survey of women with EDS or HSD to assess rates of dyspareunia and estimate rates of vulvodynia, report rates of comorbid conditions common to EDS or HSD and vulvodynia, and examine rates of conditions contributing to dyspareunia in women with EDS or HSD. Women with EDS or HSD (N = 1,146) recruited via social media were 38.2 ± 11.5 years old, primarily White (94.4%), and resided in the United States (78.5%). 63.7% of participants reported dyspareunia and 50% screened positive for vulvodynia. The rate of comorbid conditions common to EDS or HSD and vulvodynia were: irritable bowel syndrome, 6.5%; fibromyalgia, 40.0%; temporomandibular joint dysfunction, 56.4%; migraine, 6.7%; interstitial cystitis, 1.7%; and mast cell activation syndrome, 10.2%. Participants reporting dyspareunia also reported ovarian cysts, fibroids, or abdominal or pelvic scars, 47.5%; endometriosis, 26.5%; and genital lacerations, 19.3%. Women with EDS or HSD may have a higher rate of vulvodynia (50.0%) than women in the U.S. population at large (8%) and should be assessed for dyspareunia and vulvodynia.

Vulvodynia-It Is Time to Accept a New Understanding from a Neurobiological Perspective.

Vulvodynia is one the most common causes of pain during sexual intercourse in premenopausal women. The burden of vulvodynia in a woman's life can be devastating due to its consequences in the couple's sexuality and intimacy, in activities of daily living, and psychological well-being. In recent decades, there has been considerable progress in the understanding of vulvar pain. The most significant change has been the differentiation of vulvar pain secondary to pathology or disease from vulvodynia. However, although it is currently proposed that vulvodynia should be considered as a primary chronic pain condition and, therefore, without an obvious identifiable cause, it is still believed that different inflammatory, genetic, hormonal, muscular factors, etc. may be involved in its development. Advances in pain neuroscience and the central sensitization paradigm have led to a new approach to vulvodynia from a neurobiological perspective. It is proposed that vulvodynia should be understood as complex pain without relevant nociception. Different clinical identifiers of vulvodynia are presented from a neurobiological and psychosocial perspective. In this case, strategies to modulate altered central pain processing is necessary, changing the patient's erroneous cognitions about their pain, and also reducing fear avoidance-behaviors and the disability of the patient.

Vulvodynia.

Vulvodynia is a heterogenous, chronic pain condition of unknown etiology that affects 7% to 15% of women. It affects sexual function and quality of life. Vulvodynia can be primary or secondary, localized or generalized, and spontaneous or provoked. Contributing factors for provoked vulvodynia might include vulvovaginal infections, low estrogen states, and underlying anxiety disorder. Generalized vulvodynia likely arises from underlying connective tissue or neurological dysfunction. Vulvodynia treatment must be individualized on the basis of the patient's presentation and physical examination findings. Surgical excision of the vulvar vestibule has high success rates but other modalities showing success include pelvic floor physical therapy and cognitive-behavioral therapy.

Clinical outcomes and adherence to topical corticosteroid therapy in women with vulvar lichen sclerosus: A retrospective cohort study.

BACKGROUND: Vulvar lichen sclerosus is a progressive dermatitis with significant itching, pain, and sexual dysfunction. OBJECTIVE: To investigate topical steroid use and clinical improvement across multiple specialties. METHODS: Retrospective cohort study at dermatology, gynecology, and vulvovaginal specialty clinics from 2012 to 2017. Descriptive statistics and panel logistic regression were performed. RESULTS: A total of 333 women attended 1525 visits (median 6/patient; range, 1-24 visits). Patients used steroids exactly as prescribed at 66% of visits, less than prescribed at 26%, and not at all at 8%. Versus no use, exact use improved symptoms (odds ratio [OR], 4.6; 95% confidence interval [CI], 2.2-9.6) and physical examination findings (OR, 6.9; 95% CI, 2.7-17.6) more than infrequent steroid use (symptoms: OR, 2.5; 95% CI, 1.2-5.4; physical examination findings: OR, 4.2; 95% CI, 1.6-11.0). Sexual activity status was noted in 93% of vulvovaginal, 29% of gynecology, and 0% of dermatology visits. At intake, 42% of women were sexually inactive because of pain; of these, 37% became sexually active after steroid treatment. Steroid adherence was not associated with change in sexual activity. CONCLUSIONS: Women with vulvar lichen sclerosus improve more when topical steroids are used exactly as prescribed, although some improvement occurs with imperfect use. Sexual activity documentation is inconsistent, limiting quality of life follow-up.

[Vulvodynia - Diagnostics and Management Strategies]. / Vulvodynie: Diagnostik und Management.

Vulvodynia - Diagnostics and Management Strategies Abstract. Vulvodynia is characterized by chronic, idiopathic vulvar pain lasting for at least three months. After exclusion of other, specific diseases associated with vulvar pain, which can be treated accordingly, realistic therapy goals for this chronic disease should be defined. The therapy concept is multimodal, interdisciplinary as well as individualized and includes the combination of general recommendations with physiotherapeutic and psychotherapeutic measures. Pharmacological therapy, which is indispensable, is carried out off-label and includes the topical and/or systemic use of various substances and substance combinations. Surgical measures may be regarded as a possible option, especially in women with therapy-resistant and provocable vulvodynia. Alternative therapy options such as acupuncture, hypnosis and transcutaneous electrical nerve stimulation are also worth investigating.

Study on the prevalence and factors associated to vulvodynia in Spain.

OBJECTIVE: To study the prevalence and epidemiological characteristics of women with vulvodynia. To assess the risk factors associated to the disease. STUDY DESIGN: A cross-sectional study was made in which questionnaires were anonymously and confidentially distributed to Spanish women over 18 years of age between April 2016 and September 2017. The questionnaires were distributed by e-mail and through social networks, women's associations and specific websites. This type of questionnaire has been validated and used in many studies of this kind. The women answered questions referred to epidemiological aspects, demographic parameters, medical history, the presence of vulvodynia, associated factors, and comorbidities. RESULTS: A total of 684 questionnaires were completed. The prevalence of vulvodynia was 6.6% (45 women). Thirteen percent (95 women) had experienced vulvodynia at some point in life. The factors associated to vulvodynia were prior vaginal deliveries (p = 0.001), vulvovaginal candidiasis (p < 0.001) and urinary tract infections (p < 0.001). Other pain syndromes such as fibromyalgia (p = 0.012), painful bladder syndrome/ interstitial syndrome (p < 0.001), temporomandibular joint pain (p = 0.021), coxofemoral pain (p = 0.001) or headache (p = 0.001) have also been associated to vulvodynia. CONCLUSIONS: The prevalence of vulvodynia in Spain is similar to that found in other countries. Many factors are involved in its development and persistence, particularly the presence of other pain syndromes and recurrent infections that could trigger complex inflammatory reactions.

Sexual pain and IC/BPS in women.

Interstitial cystitis/bladder pain syndrome (IC/BPS) and female sexual dysfunction (FSD) are common conditions that substantially reduce women's health. In particular, women with IC/BPS show vulvodynia, a kind of FDS that originates from consistent pain around the vulvar area. There have been many studies attempting to find the underlying mechanisms that induce the chronic pain associated with IC/BPS and vulvodynia and explain why these two conditions often coexist. Proposed theories suggest that pain hypersensitivity is being mediated by peripheral and central sensitization. However, there are still many unknown factors, such as etiologies, that can evoke pain hypersensitivity and may be linking the casual relationship between IC/BPS and vulvodynia. At present, knowledge regarding IC/BPS and vulvodynia are insufficient when considering their clinical importance. Therefore, efforts are necessary to elucidate the issues surrounding IC/BPS and vulvodynia.

Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia.

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8+CD103+ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ9-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.