Abstract
Vulvar pruritus is an unpleasant sensation and frequent symptom associated with many dermatologic conditions, including infectious, inflammatory and neoplastic dermatoses affecting the female genitalia. It can lead to serious impairment of quality of life, impacting sexual function, relationships, sleep and self-esteem. In this review, common conditions associated with vulvar itch are discussed including atopic and contact dermatitis, lichen sclerosus, psoriasis and infectious vulvovaginitis. We review the potential physiologic, environmental and infectious factors that contribute to the development of vulvar itch and emphasize the importance of addressing their complex interplay when managing this disruptive and challenging symptom.
Introduction
Vulvar pruritus is a frequently chronic and debilitating symptom associated with many vulvar disorders. The exact prevalence of vulvar pruritus is unknown as epidemiologic data are limited and most reports focus on individual conditions involving genital itch. In a study that surveyed 480 women from the general population in Boston, Massachusetts, 6.6% of women reported experiencing vulvar itch or burning (). This is similar to rates of vulvar pruritus reported amongst the general German population, which was noted to range from 5 to 10% (). The true prevalence of vulvar pruritus may be difficult to assess as it is likely underreported given the embarrassment many women feel when discussing genital symptoms (). Itch was found to be the most frequent symptom, occurring in 70% of patients presenting to a clinic specializing in vulvar conditions (). Similarly, in a survey study performed in the United Kingdom, 67.3% of general practitioners reported that they see more than five patients per month with vulvar symptoms, with vulvar pruritus being the most common ().
Vulvar pruritus can have a profound impact on quality of life (). In patients with genital psoriasis, itch was reported to be the most bothersome symptom with substantial impact on sexual relationships and psychosocial well-being (). Moreover, several studies have demonstrated the negative impact of lichen sclerosus, a condition characterized by genital itch and pain, on sexual satisfaction (–).
Pruritic Vulvar Dermatoses
Vulvar pruritus arises in the setting of many inflammatory, infectious, and neoplastic processes that can affect the female genitalia ().
Inflammatory
Common Etiologies
Common inflammatory vulvar dermatoses characterized by marked pruritus include atopic and contact dermatitis, lichen planus, lichen simplex chronicus, psoriasis and lichen sclerosus, among others. Atopic dermatitis (AD), irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) are the most common causes of vulvar itch in women (). In one study of 144 adult women with vulvar complaints, 66% of patients had an eczematous process confirmed on pathology (). In a separate prospective cohort study, 81.4% of patients with vulvar itch were found to have at least one positive contact allergen on patch testing (). Similarly, AD and ICD have been reported to be the most common cause of vulvar symptoms in prepubertal girls ().
AD is a genetic skin disease characterized by an altered skin barrier and chronic pruritus. It presents acutely as erythematous edematous or vesiculated plaques. Lichenification and dyspigmentation may be observed in chronic cases. It is important to note that due to the altered skin barrier, patients with AD may be at higher risk for the development of both irritant and allergic contact dermatoses (–).
Contact dermatitis consists of inflammation of the skin resulting from an external agent that acts as an irritant or as an allergen. The manifestation of both forms of dermatitis is very similar, varying from mild erythema and scaling to more severe erythema and edema (). The area of involvement may be localized to the exposed site or be more extensive as the product spreads, with moisture or scratching (). In addition to itch, pain and burning may also be present. Ulceration and erosions may be seen with primary irritants (). In ACD, vesiculation in the acute phase may be observed (). In more chronic cases, lichenification with excoriation are common features. Secondary infection can be seen in both ICD and ACD with pustules, crusting and fissuring.
Many substances can cause irritation of the vulva, including body fluids, feminine hygiene products or various topical medications (). Physical and thermal irritants like tight fitting clothes, wash cloths, sponges and hair dryers have been implicated in ICD development (, ). Similarly, allergens often contribute to itch and dermatitis in patients with vulvar disease. Common allergens include fragrances and preservatives in products like soaps and detergents, cleansing wipes, antiseptics, spermicides, sanitary pads, lubricants, and even topical treatments like steroids, anesthetics, antibacterial and antifungal agents (, ). Rubber products, like pessaries, condoms, diaphragms, and gloves may also be sensitizers (). Additionally, pantyhose and clothing with azo dyes may contribute to ACD (). Patch testing may identify the allergens responsible for ACD.
Lichen simplex chronicus (LSC), or circumscribed neurodermatitis, is an eczematous disorder that commonly affects vulvar skin. It presents as scaly, thickened plaques that develop in response to persistent and vigorous scratching of intensely pruritic sites (). LSC accounts for 35% of patient visit to vulvar specialty clinics, predominately affecting adult women but may also occur in children (). Although often considered a primary diagnosis, LSC often arises as a secondary finding in the setting of neuropathic or other underlying primary cutaneous diseases such as AD, ACD or LP (). It can also occur in patients with psychiatric disorders like depression and obsessive-compulsive disorder (, ). Pruritus in systemic diseases such as end stage renal disease, obstructive biliary disease or Hodgkin's lymphoma can also provoke LSC (). LSC is characterized by a self-perpetuating itch-scratch cycle. In patients with primary LSC, the itch-scratch cycle is often triggered by initial skin irritation from tight-fitting clothing, irritating fabrics or personal care items which provoke scratching (, ). Damage to the vulvar epithelium due to scratching compromises the skin barrier, potentially provoking release of epithelial cytokines and making the skin more vulnerable to potential infection, which in turn drives itch and inflammation (). If sufficiently pronounced, scratching results in hypertrophy and lichenification of the genital skin. Clinical examination usually reveals lichenified plaques with excoriations and variable levels of erythema and scale ().
Psoriasis is another common inflammatory skin disease that affects genital skin and is often accompanied by pruritus (). In most cases, genital psoriasis arises in the setting of more widespread cutaneous involvement, but isolated presentation of genital psoriasis may occur in 2–5% of psoriatic patients (). Psoriatic lesions of the vulva are more common in children than in adults. In a study that evaluated 130 prepubertal girls with vulvar complaints, 17% had psoriasis, which was the third most common cutaneous condition after AD and LS (). Clinical features of vulvar psoriasis consist of well-demarcated, brightly erythematous plaques with or without scale on the labia majora (). Plaques may extend to the inguinal folds and maceration may be present ().
Lichen sclerosus (LS) is another inflammatory dermatosis that affects the vulvar and vaginal mucosa, and not uncommonly extends to the perineum and perianal skin. While vulvar LS can occur at any age, most cases are observed in prepubertal girls or in postmenopausal women, when endogenous estrogen production is low (). Pruritus and pain are predominant symptoms of the disease, although rarely LS may be asymptomatic. Other symptoms include dyspareunia and dysuria. In children, constipation may be a presenting symptom due to pain with defecation (). The exact prevalence of LS is unknown, but estimates range from 1:300 to 1:1,000 of all adult patients referred to dermatology departments (). The estimated prevalence in prepubertal girls is 1 in 900 (). At a general gynecology practice, the rate of vulvar LS was estimated to be 1.7% (). Again, the discrepancy in reported prevalence among gynecology and dermatology practices may reflect the hesitance of patients to discuss genital symptoms outside of a dedicated health visit focused on genitourinary care. LS typically manifests as atrophic, pale to white patches or plaques that often form a figure-of-eight pattern encompassing the vulva and anus (). Erosions and painful fissures may be observed due to underlying inflammation as well as scratching or irritation of the inflamed, fragile tissue. Loss of normal vulvar architecture may be observed in more advanced cases, with burying of the clitoris and agglutination of the labia. Lichen sclerosus is associated with increased risk of developing genital squamous cell carcinoma (SCC). While the exact risk of malignant transformation is uncertain, estimates of the development of SCC are between 3 and 5% (, ). In a more recent study that used data from the Dutch Pathology Registry and included 3,038 women diagnosed with lichen sclerosus, the risk of SCC development after 10 and 20 years was 3.3 and 6.7%, respectively ().
Lichen planus (LP) is a highy pruritic, autoimmune mucocutaneous disorder in which activated T-cells target basal keratinocytes of keratinized and non-keratinized squamous epithelium (). The prevalence of LP is estimated to be 1% of the general population (). Although LP most commonly affects the oral mucosa, ~25% of women with oral LP also have vulvovaginal involvement (). LP predominately affects adult women, although isolated cases have been reported in young girls (). Vulvovaginal LP may manifest in several ways, presenting in erosive, papulosquamous, and hypertrophic forms (). Erosive LP, the most common presentation affecting genital skin, is characterized by well-demarcated glassy, erythematous to violaceous patches with a hyperkeratotic border and primarily affects the non-keratinized epithelium of the vestibule, labia minora and vagina (). Several cohort studies have examined the distribution of LP subtypes arising on keratinized skin of the labia majora (, ). Papulosquamous LP, also referred to as classic LP, arises in 4–33% of cases and manifests with purple, brown or pink polygonal papules or small plaques which may have associated Wickham's striae (, ). Hypertrophic lichen planus arises in 29–46% of cases and presents with thicker, violaceous and hyperkeratotic plaques (). One cohort study describing clinical and histologic features in 63 vulvar LP cases reported pruritus as the primary symptom affecting 79 and 81% of hypertrophic and papulosquamous LP patients, respectively, while pain was a primary manifestation in only 10 and 14%, respectively (). Similar to LS, longstanding and untreated disease may lead to alterations in the normal architecture with narrowing of the vaginal introitus ().
Other Etiologies
Inflammatory vulvar pruritus may also be caused by seborrheic dermatitis, plasma cell vulvitis, and Fox-Fordyce disease. Seborrheic dermatitis is an inflammatory condition that affects the sebum-rich areas of the body and should be considered in patients with vulvar pruritus. While uncommon, seborrheic dermatitis can occasionally present on the vulva, and is usually associated with simultaneous appearance of characteristic seborrhea on the scalp and face (). It manifests on the vulva as erythematous plaques mainly on the labia, majora, perineum, and mons pubis. Scale is frequently absent in the vulva and the severity of pruritus is often more marked than would be expected based on the clinical signs ().
Plasma cell vulvitis (PCV) is an extremely rare cause of vulvar pruritus characterized by a well-circumscribed erythematous plaque composed of predominately plasma cells (, ). It is typically located within the vulvar vestibule, often extending to the medial labia minora. The most common symptoms associated with PCV are pruritus, pain, burning, and dyspareunia ().
Fox-Fordyce disease is another rare inflammatory condition which can affect vulvar skin and may provoke intense itching. The primary pathophysiologic process involves obstruction of the apocrine sweat duct and subsequent ductal rupture causing inflammation and enlargement of the glands (). The mons pubis and labia majora are most commonly affected. Clinically, Fox-Fordyce disease manifests as intensely pruritic, numerous, flesh-colored to slightly yellow papules (, ).
Infectious
Common Etiologies
Vulvar pruritus may be associated with several types of infections and these vary with age. In prepubertal females, infection with Group A beta-hemolytic streptococcus (GABHS) commonly provokes vulvar symptoms including pruritus and pain, and manifests with sharply demarcated, edematous, red plaques (). In contrast, adult women are less susceptible to acute GABHS-mediated vulvitis. Oropharyngeal GABHS infection often, but not always, precedes the development of vulvar symptoms ().
In adult women, vulvovaginal candidiasis is a frequent cause of vulvar pruritus, with some studies suggesting candidiasis accounts for 35–40% of vulvar itch cases in this age group (). Multiple epidemiologic studies have indicated that Candida albicans is responsible for the excess of episodes of vulvovaginal candidiasis, although reports indicate than non-albicans Candida species, notably Candida glabrata, account for 10–20% of episodes in certain regions (–). Increased estrogen levels, which have been implicated in reducing the inhibitory activity of epithelial cells against Candida, are thought to account for the rise in candidiasis in women of reproductive age (). It is estimated that 75% of women have been affected by vulvovaginal candidiasis at some point in their lifetime (, ). Pregnancy, antibiotics, oral contraceptives and hormonal replacement therapies may increase estrogen levels resulting in an increased frequency of disease (, ). Tamoxifen, an estrogen antagonist in breast tissue, has been reported to have estrogen-like effects on vaginal epithelium in postmenopausal women, increasing risk of vulvovaginal candidiasis (–). In addition, compromised immune function is also associated with increased risk of yeast infections, as has been observed in patients with diabetes, HIV or who regularly use systemic or topical corticosteroids (). Patients with recurrent candidal vulvovaginitis, defined as the occurrence of at least four episodes in 1 year, may have a predisposing genetic factor underlying their susceptibility (). Clinical presentation of vulvar erythema, pustules or erosions and vaginal discharge may vary, but symptoms of pruritus and burning are commonly observed. Additional symptoms may include dysuria and dyspareunia. Identification of the specific Candida species can be considered in patients with refractory or recurrent vulvovaginal candidiasis as some species are often resistant to treatment ().
Other Etiologies
In contrast to GABHS, which commonly affects prepubertal females, Staphylococcus aureus, Haemophilus and Shigella infections are less common infectious causes of vulvovaginal pruritus (). Enterobius vermiuclaris (pinworm) infestation may be another source of vulvar and perineal pruritus in younger females worldwide ().
In adults, the two most common parasitic vulvar infestations are pediculosis pubis (pubic lice) and scabies (). Both cutaneous infections are often seen in young adults and are typically acquired during sexual contacts. Vulvar pruritus is the predominant symptom that develops following allergic sensitization (, ). In pediculosis pubis, adult lice and their eggs (nits) can be visible to the naked eye. Infection may spread from the genital area to other parts of the body, such as the thighs or trunk (). Infestation with scabies causes widespread itching with nocturnal predominance. Unlike in other areas of the body, burrows on the vulva are uncommon and may be masked by excoriations or secondary infection ().
Tinea cruris is an additional infection that can cause vulvar pruritus in women (, ). It can involve the inguinal creases and the labia majora. The typical lesions consist of mildly pruritic plaques with a raised erythematous scaly edge and central clearing. Viral infections, such as herpes simplex virus (HSV), human papilloma virus (HPV), and molluscum contagiosum may also trigger a sensation of vulvar itch (). However, herpetic infections predominately manifest as pain, and HSV and molluscum are typically asymptomatic.
Neoplastic
Benign or malignant neoplasms are uncommon causes of vulvar pruritus. Rarely, pruritus may be an indication of vulvar malignancy such as SCC, melanoma, extramammary Paget's disease (EMPD) or vulvar intraepithelial neoplasia (VIN). Vulvar malignancy is uncommon and represents approximately 2–5% of all gynecologic cancers, with SCC representing the vast majority (>80%) of cases, followed by melanoma, BCC, verrucous carcinoma, EMPD, adenocarcinoma and Bartholin gland carcinoma (). Although frequently overlooked, pruritus is the most common initial symptom of vulvar malignancy, with reports of up to 50–60% of patients endorsing moderate to severe pruritus (, ). In a multi-center, retrospective study describing 76 women with vulvar cancer in Tunisia, 48.7% of patients experienced chronic pruritus as the presenting symptom and the mean interval of time from symptom onset to cancer diagnosis was ~12.9 months (+/– 6.38) (). Squamous cell carcinoma typically presents as persistent papules, plaques or ulcers with associated bleeding, itch and/or pain that is refractory to anti-inflammatory treatment (). It is more common in postmenopausal women and is often associated with LS. Paget's disease of the vulva is an uncommon lesion that represents <1% of vulvar neoplasms (). It predominately affects postmenopausal Caucasian women and presents as a white to red, velvety pruritic thin plaques (). Although usually confined to the epithelium, invasive disease is observed in 15–25% of patients (). VIN is a premalignant finding and is associated with HPV infection, particularly subtypes 16 and 18 (). It can cause itch leading to varying degrees of excoriation and crusting ().
Additionally, a variety of benign neoplastic processes may contribute to vulvar pruritus. For example, syringomas are rare tumors derived from eccrine sweat glands. While they typically involve the face, neck or chest, they occasionally present as multiple small, flesh-colored pruritic papules on the vulva (). Moreover, hidradenoma papilliferum (HP), a tumor thought to originate from apocrine glands or mammary glands, can occasionally occur on the vulva and cause pruritus (). In one series, HP represented up to 60% of vulvar adnexal tumors (). It usually manifests as a firm, flesh to red-colored nodule that may or may not be accompanied with pruritus (). It can be confused with adenocarcinoma due to its tendency to ulcerate (, ).
Pathophysiology of Vulvar Itch
Impaired Barrier Function
Many pruritic vulvar disorders, such as atopic dermatitis and psoriasis, are associated with altered skin barrier function (). Disruption of the skin barrier can be caused from a variety of factors including epidermal inflammation and mechanical or environmental insults, which in turn activate itch receptors (). The barrier function of vulvar skin is substantially weaker than at other anatomical sites, and thus may be particularly prone to developing pruritus. The rate of transepidermal water loss (TEWL), a marker of barrier function, is significantly higher in vulvar skin than the skin of other cutaneous sites such as the forearm, suggesting a weaker epidermal barrier at the vulva (, ). Indeed, several studies have shown vulvar skin to be more reactive to irritants compared to other skin areas. In one study, two irritants, bezalkonium chloride and maleic acid, were applied the labia majora and forearm, and the intensity of skin reactions were assessed (). Vulvar skin was found to be significantly more reactive than forearm skin to the two irritants, although this reactivity was not reproduced in studies with another irritant, sodium lauryl sulfate (). Sweat, urine, friction by clothes and feminine hygiene products may all contribute to vulvar irritation by weakening barrier function (). Moreover, low estrogen levels occurring with menopause, breast-feeding, postpartum and medications can also result in impaired barrier function as estrogen is important to maintain the structural integrity of the vulvovaginal space (). Thinning of the vulvar epithelium in postmenopausal women combined with elevated skin pH and reduced corneum hydration cause barrier dysfunction ().
Once disrupted, the skin barrier is more susceptible to exogenous and endogenous itch-triggers. In addition to the potential itch or pain associated with microbial colonization, mechanical irritation and chemical injury discussed above, epithelial damage leads to immune activation via release of skin-specific cytokines, including thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33, which directly activate pruriceptive afferent nerve fibers (, ). Moreover, cysteine and serine proteases, such as cathepsin S and various kallikreins (KLKs), may be released by keratinocytes upon barrier disruption and are capable of directly stimulating or modulating itch via activation of Mas-related G-protein coupled receptors (MRGPRs) and protease-activated receptors (PARs) (–).
Neural Dysfunction
Neural dysfunction, due to neurogenic or neuropathic insults, is common but often-overlooked cause of vulvar pruritus. Neurogenic itch originates from endogenous or exogenous factors that activate the central nervous system at the level of the brain or spinal cord without evidence of nerve damage (). Growing evidence suggests that neurogenic factors may contribute to vulvar pruritus. Epithelial and stromal tissue of the vulvar skin and vaginal mucosa express the transient receptor potential cationic channel type A1 (TRPA1), a channel known for its role in mediating and modulating non-histaminergic itch (). Animal models of neonatal vaginal irritation suggest that hypersensitivity of the vagina is driven in part by increased hypothalamic-pituitary-adrenal (HPA) axis activation and subsequent increases in TRPA1 expression and functional activity in nerve terminals innervating the vaginal mucosa (). Similarly, separate studies have demonstrated that expression of the transient receptor potential vanilloid 1 (TRPV1) ion channel, also well-known for its role in modulating pain and itch signals, is increased in vulvovaginal epithelia in patients with vulvodynia compared to controls (, ). Although vulvodynia is classically regarded as a type of neuropathic pain, itch and burning can accompany vulvodynia in 20 and 70%, respectively (). Future studies will be needed to specifically evaluate whether the expression and function of TRP ion channels as well as primary itch-sensing receptors are altered in disorders associated with vulvar pruritus.
In contrast to neurogenic pruritus in which neural architecture is considered normal but stimulated abnormally, neuropathic pruritus results from injury or damage to nerve fibers. Small fiber polyneuropathy (SFPN), which affects the small, unmyelinated C-fibers and thinly myelinated A-delta fibers that conduct itch and pain may arise secondary to systemic diseases such as diabetes mellitus, sarcoidosis, amyloidosis, B12 deficiency, and viral infections, among others (). While individuals with SFPN usually present with symptoms in their distal extremities or generalized symptoms, itch can also be localized entirely to the vulva. Vulvar itch may also be caused by nerve or nerve root compression at the levels of L4 through S2 vertebrae secondary to spinal injuries or lumbosacral arthritis (, , ). Another source of potential nerve irritation or injury may be caused by reactivation of varicella zoster, as 8.4% of shingles cases affect the dermatomes that innervate the vulva (). Despite a robust immune response, long-lasting damage to the affected nerves may result in persistent pain and/or itch in affected vulvar skin (). It is estimated that 30% of people with post-herpetic neuralgia suffer from itch (), and thus postherpetic itch (PHI) should be considered in women presenting with genital pruritus.
Hormonal Influence
Hormonal changes play an important role in regulating vulvar epithelium by influencing vaginal pH and microflora composition. Similar to the vagina, vulvar pH is related to hormonal status and will change over a lifetime (). In childhood, the vulvar and vaginal epithelia are neutral or alkaline, due to a lack of acid-producing vaginal microbes, lactobacilli (). With the onset of menstruation, cyclic changes in estrogen and progesterone create a new epithelial micro-environment. Estrogen stimulation increases glycogen levels in the vulvar epithelium and lactobacilli subsequently colonize the vulvovaginal area, causing the pH to decrease (). During parts of the menstrual cycle and following menopause, decreases in systemic estrogen result in an increase in vulvovaginal pH.
At more alkaline pH, the activity of various epithelial or immune-cell derived proteases may increase and thereby lead to greater activation of neuronal itch receptors (, ). Consistent with this hypothesis, abnormal expression of proteases and PAR activation has been implicated in several pruritic inflammatory skin disorders, such as AD and psoriasis (–). In addition to their effects on neuronal PARs, serine proteases such as KLKs and mast cell tryptase may also activate PARs expressed by keratinocytes or endothelial cells, stimulating the release of neuropeptides and cytokines which drive neurogenic inflammation and further propagation of endogenous pruritogens (–). Furthermore, the interactions between proteases and their endogenous inhibitors, present in the skin to ensure skin homeostasis, are influenced by the pH, with the greatest inhibitory capacity occurring in neutral pH environments (124). Thus, fluctuations in vulvovaginal pH due to hormonal status could shift the balance between protease and protease inhibitor activity, further contributing to PAR-mediated inflammation and itch.
Microbiome
The composition of the human vaginal microbiome may contribute to the pathogenesis of vulvar pruritus, particularly with respect to itch triggered by the mucocutaneous pathogens discussed previously. Interestingly, compared to the microbiota that colonize other regions of the body, such as the oropharynx and gut, the vaginal microbiome exhibits much lower diversity with Lactobacillus as the dominating species (125). Vaginal pH correlates with microbiome composition. Indeed, the composition of the vulvovaginal microbiome is dynamic and influenced by hormone-driven pH changes throughout the woman's reproductive life (126). Lactobacillus dominance increases with high estrogen levels because of proliferation and accumulation of glycogen. Ethnic differences also correlate with microbiome composition, with Blacks and Hispanics demonstrating higher levels of anaerobic bacterial species (125–127). By acidifying the vagina and producing antimicrobial substances, such as lactic acid and hydrogen peroxide, lactobacilli protect against opportunistic infections (). Similarly, in keratinized squamous epithelia like that of the labia majora, resident microbiota such as Cutibacterium acnes promotes reduces skin pH via production of short-chain fatty acids (128). Other commensal microbes, such as Staphylococcus epidermidis, not only produce biofilms and other enzymes that enhance the function of antimicrobial peptides (AMPs) such as human b-defensins (HbDs) against dysbiosis, but also promote production of anti-inflammatory cytokines such as IL-10 from antigen presenting cells and reduce pro-inflammatory signals released by keratinocytes (129, 130).
Dysbiosis may lead to pruritus or sensory disturbance via multiple mechanisms. First, bacterial and viral pathogens directly engage keratinocytes via cell surface toll-like receptors (TLRs), triggering their release of the alarmins TSLP and IL-33 as well as AMPs such as HbDs and canthelicidins. While the alarmins directly activate itch by binding to their receptors on peripheral afferents (, ), they also initiate TH2 immune cascades that contribute to barrier inflammation that fuels ongoing pruritus (131). Keratinocyte-derived AMPs trigger itch indirectly by stimulating mast cell release of histamine and IL-31 which in turn activate pruriceptors (132). Moreover, mast cells may also detect microbiota via their own TLRs or their ability to respond to a host of endogenous molecules released as part of a coordinated tissue response to infection including substance P and complements (133). Consistent with these data, derived primarily from animal models and human studies in allergic disorders, one study found that compared to healthy controls, women with LS has increased expression of AMPs including HbD-2 and psoriasin (134).
Pathogenic bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa and others have also been shown to directly activate peripheral afferent nociceptive fibers (135). In animal models, bacteria-derived N-formylated peptides and the pore-forming toxin a-haemolysin stimulated calcium influx in nociceptive dorsal root ganglia by binding to neuronal formyl-peptide receptor 1 or by direct pore-formation, respectively (135). Once activated, nociceptors are capable of releasing neuropeptides that in turn modulate the inflammatory response, which may further influence the development of pain and/or itch. Similarly, in colonic epithelium, bacterial cell products have also been shown to directly activate dorsal root ganglion neurons and subsequently trigger elaboration of inflammatory cytokines (136). In addition, lipopolysaccharide (LPS) contained in the cell envelope of Gram-negative bacteria is also capable of stimulating calcium influx in trigeminal dorsal root ganglia neurons and sensitizing TRPV1 via a TLR4-mediated mechanism (137). How these processes specifically contribute to the development of itch or sensory disturbance in vulvovaginal epithelia remains to be examined.
Management Considerations
Recognizing the numerous factors that contribute to the pathogenesis of vulvar pruritus is crucial for appropriate diagnostic evaluation and management. The approach to therapy should be directed against the primary underlying mechanism suspected (e.g., inflammation due to AD or ACD, candidiasis, etc), but must also account for other exacerbating factors.
Pharmacologic Treatments
Topical corticosteroids are commonly used to alleviate itch caused by inflammatory skin disease (). The potency used in a patient should be determined based on the age of the patient, diagnosis and severity of symptoms. Some vulvar conditions, such as LS and LP, may require more potent or prolonged corticosteroid therapy like clobetasol and halobetasol, whereas a less potent formulation may be sufficient for other diagnoses (). The topical calcineurin inhibitors, tacrolimus or pimecrolimus, are non-steroidal anti-inflammatory agents that may also be useful in reducing vulvar inflammation or pruritus, particularly when prolonged courses are required to avoid steroid-induced side effects. Additional topical therapy targeting pruritus may be considered, for instance capsaicin or doxepin preparations (). Doxepin should be used with caution due to high sensitizing capacity (138, 139). If capsaicin cream is being considered for use on genital skin, lower concentrations (0.012%) are advised (140). Systemic steroid preparations should be considered only after topical approaches have been exhausted or in severe dermatitis. Systemic immunomodulators, such as azathioprine, methotrexate, mycophenolate mofetil and infliximab have been evaluated for their potential use in AD, however further research is needed to specifically determine their utility in pruritic vulvar dermatoses (141–144).
Excoriated epidermis can become superinfected, and thus practitioners should have a low threshold to investigate and treat potential fungal and/or bacterial superinfections even when women have other underlying reasons for genital pruritus. For infectious causes of vulvar pruritus, treatment should depend on the inciting pathogen. Specific single bacterial infections require appropriate topical or oral antibiotics. For fungal infections like candidiasis, topical or oral azole agents are effective. There is no evidence to suggest that a specific azole results in better cure rates (, 145). However, it is important to note that Candida glabrata is less responsive to azoles. Vaginal boric acid or amphotericin B can be used for refractory cases (). Treatment of pediculosis and scabies infestations is best accomplished with permethrin or pyrethrins with piperonyl butoxide (146). Accepted therapies for pinworms include pyrantel pamoate or mebendazole, which should be administered to all household members (147). For viral causes of vulvar pruritus, acyclovir or valacyclovir are considered standard treatment for genital herpes (147). In patients with condyloma acuminatum caused by HPV infection, treatment with podophyllin, liquid nitrogen, or imiquimod are effective (147).
Although few studies address using neuromodulators for neuropathic vulvar itch, some reports suggest that oral gabapentin and topical lidocaine may be effective (148, 149). Use of tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants may also be considered and have shown benefit in patients with chronic itch and prurigo (). In postmenopausal women or in the setting of a hypoestrogenic state, topical estrogen therapy may be suitable to reduce symptoms of dryness, atrophy and pruritus. As our understanding of itch pathophysiology grows, targeted anti-pruritic treatments may emerge and will need to be evaluated in randomized control trials for vulvar pruritus.
Non-pharmacologic Treatments
Because barrier dysfunction arises so frequently in conditions associated with vulvar pruritus, it is important to counsel patients to avoid all sources of irritation or potential allergic sensitization, including fragrances, lubricants and cleaning products. Patch testing should be performed for patients with physical exam or histologic findings suspicious of allergic contact dermatitis. Patch testing may also be a useful tool in patients with persistent vulvar symptoms that is unresponsive to treatment after 8 weeks, to avoid delays in diagnosis (150). Simple steps of cleansing with mild or no detergents when bathing and rinsing genital skin with water following urination when possible should be emphasized. Moreover, lipid-replenishing formulations such as petrolatum or barrier creams such as zinc oxide paste should be used to enhance barrier function of the vulvar skin and mucosa.
Behavioral modification strategies, such as skin rubbing and cooling rather than scratching can be effective when used in combination with pharmacotherapy. Patients should also be advised to keep fingernails short to minimize trauma caused by excoriation. Moreover, psychological interventions to control the urge to scratch, such as cognitive behavioral therapy, may be beneficial for some patients. A randomized controlled trial with AD patients receiving cognitive-behavioral treatment have shown significantly decreased itch intensity and scratching behavior after 1 year, as compared to those receiving only standard dermatologic care (151).
Phototherapy is another therapeutic modality that may be considered for the management of itch in various inflammatory pruritic conditions affecting the vulva, such as AD, psoriasis and LS (152). Several studies have documented the efficacy of phototherapy at various wavelengths for improving AD severity and associated pruritus, with medium-dose ultraviolet A (UVA) and narrowband UVB (NBUVB) being the preferred modalities (152–155). Similarly ultraviolet B (UVB) has been shown to reduce itch in psoriasis patients (156). Phototherapy on genital skin may best be considered in refractory cases and when handheld devices are available.
Conclusions
Vulvar pruritus is a common symptom of multifactorial etiology that may be driven by primary inflammatory disorders, barrier disruption, hormonal changes and infectious causes. Vulvar itch has a significant impact on the quality of life of affected patients and should be addressed by gynecologists, dermatologists, urologists and general practitioners when possible. Effective therapeutic strategies require that practitioners understand the multidimensional nature of vulvar pruritus and simultaneously address the many contributing factors that underly this challenging symptom.
Statements
Author contributions
HR conducted the literature review and drafted the manuscript. SE participated in reviewing and revising the manuscript. Both authors read and approved the final version of the manuscript including references.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1.
HarlowBLWiseLAStewartEG. Prevalence and predictors of chronic lower genital tract discomfort. Am J Obstet Gynecol. (2001) 185:545–50. 10.1067/mob.2001.116748
2.
WoelberLPrieskeKMendlingWSchmalfeldtBTietzH-JJaegerA. Vulvar pruritus-causes, diagnosis and therapeutic approach. Dtsch Arztebl Int. (2020) 116:126–33. 10.3238/arztebl.2020.0126
3.
GokdemirGBaksuBBaksuADavasIKosluA. Features of patients with vulvar dermatoses in dermatologic and gynecologic practice in Turkey: is there a need for an interdisciplinary approach?J Obstet Gynaecol Res. (2005) 31:427–31. 10.1111/j.1447-0756.2005.00314.x
4.
SullivanAKStraughairGJMarwoodRPStaughtonRCBartonSE. A multidisciplinary vulva clinic: the role of genito-urinary medicine. J Eur Acad Dermatol Venereol. (1999) 13:36–40. 10.1111/j.1468-3083.1999.tb00841.x
5.
KandanearachchiPSahuBAntonakouAPapoutsisD. A survey of management of vulvar disorders in the primary health care setting in an urban area of England. Arch Hell Med. (2018) 35:405–11. Available online at: http://www.mednet.gr/archives/2018-3/pdf/405.pdf
6.
HickeySBellH. Quality of life in the vulvar clinic: a pilot study. J Low Genit Tract Dis. (2010) 14:225–9. 10.1097/LGT.0b013e3181dc1e45
7.
CatherJCRyanCMeeuwisKPotts BleakmanAJNaegeliANEdson-HerediaEet al. Patients' perspectives on the impact of genital psoriasis: a qualitative study. Dermatol Ther. (2017) 7:447–61. 10.1007/s13555-017-0204-3
8.
HaefnerHKAldrichNZDaltonVKGagnéHMMarcusSBPatelDAet al. The impact of vulvar lichen sclerosus on sexual dysfunction. J Womens Health. (2014) 23:765–70. 10.1089/jwh.2014.4805
9.
FelminghamCChanLDoyleLWVeyseyE. The Vulval Disease Quality of Life Index in women with vulval lichen sclerosus correlates with clinician and symptom scores. Australas J Dermatol. (2020) 61:110–8. 10.1111/ajd.13197
10.
VittrupGMoerupLHeilesenTJensenDLaursenBSWestmarkSet al. PO-02-015 Quality of life and sexuality in Danish women with lichen sclerosus. J Sex Med. (2019) 16:S80. 10.1016/j.jsxm.2019.03.256
11.
SavasJAPichardoRO. Female genital itch. Dermatol Clin. (2018) 36:225–43. 10.1016/j.det.2018.02.006
12.
FischerGO. The commonest causes of symptomatic vulvar disease: a dermatologist's perspective. Australas J Dermatol. (1996) 37:12–8. 10.1111/j.1440-0960.1996.tb00988.x
13.
FischerGSpurrettBFischerA. The chronically symptomatic vulva: aetiology and management. Br J Obstet Gynaecol. (1995) 102:773–9. 10.1111/j.1471-0528.1995.tb10841.x
14.
HaverhoekEReidCGordonLMarshmanGWoodJSelva-NayagamP. Prospective study of patch testing in patients with vulval pruritus. Australas J Dermatol. (2008) 49:80–5. 10.1111/j.1440-0960.2008.00442.x
15.
FischerGRogersM. Vulvar disease in children: a clinical audit of 130 cases. Pediatr Dermatol. (2000) 17:1–6. 10.1046/j.1525-1470.2000.01701.x
16.
MilamECJacobSECohenDE. Contact dermatitis in the patient with atopic dermatitis. J Allergy Clin Immunol Pract. (2019) 7:18–26. 10.1016/j.jaip.2018.11.003
17.
KohliNNedorostS. Inflamed skin predisposes to sensitization to less potent allergens. J Am Acad Dermatol. (2016) 75:312–7.e1. 10.1016/j.jaad.2016.03.010
18.
ShaughnessyCNMalajianDBelsitoDV. Cutaneous delayed-type hypersensitivity in patients with atopic dermatitis: Reactivity to surfactants. J Am Acad Dermatol. (2014) 70:704–8. 10.1016/j.jaad.2013.12.009
19.
MachlerBCSungCTDarwinEJacobSE. Dupilumab use in allergic contact dermatitis. J Am Acad Dermatol. (2019) 80:280–1.e1. 10.1016/j.jaad.2018.07.043
20.
MargessonLJ. Contact dermatitis of the vulva. Dermatol Ther. (2004) 17:20–7. 10.1111/j.1396-0296.2004.04003.x
21.
BauerARodigerCGreifCKaatzMElsnerP. Vulvar dermatoses–irritant and allergic contact dermatitis of the vulva. Dermatology. (2005) 210:143–9. 10.1159/000082570
22.
ConnorCJEppsteinerEE. Vulvar contact dermatitis. Proc Obstet Gynecol. (2014) 4:1–14. 10.17077/2154-4751.1255
23.
RimoinLPKwatraSGYosipovitchG. Female-specific pruritus from childhood to postmenopause: clinical features, hormonal factors, and treatment considerations. Dermatol Ther. (2013) 26:157–67. 10.1111/dth.12034
24.
PattersonJW. Weedon's Skin Pathology. 4th ed. Charlottesville, VA: Elsevier (2016).
25.
LynchPJ. Lichen simplex chronicus (atopic/neurodermatitis) of the anogenital region. Dermatol Ther. (2004) 17:8–19. 10.1111/j.1396-0296.2004.04002.x
26.
ThorstensenKABirenbaumDL. Recognition and management of vulvar dermatologic conditions: lichen sclerosus, lichen planus, and lichen simplex chronicus. J Midwifery Womens Health. (2012) 57:260–75. 10.1111/j.1542-2011.2012.00175.x
27.
CharifaABadriTHarrisBW. Lichen Simplex Chronicus. In: StatPearls. Treasure Island (FL): StatPearls Publishing. (2020).
28.
KonukNKocaRAtikLMuhtarSAtasoyNBostanciB. Psychopathology, depression and dissociative experiences in patients with lichen simplex chronicus. Gen Hosp Psychiatry. (2007) 29:232–5. 10.1016/j.genhosppsych.2007.01.006
29.
BologniaJLSchafferJVCerroniL editors. Dermatology E-Book. 4th ed. New Haven, CT: Elsevier (2017).
30.
CorazzaMBorghiAMinghettiSToniGVirgiliA. Effectiveness of silk fabric underwear as an adjuvant tool in the management of vulvar lichen simplex chronicus: results of a double-blind randomized controlled trial. Menopause. (2015) 22:850–6. 10.1097/GME.0000000000000410
31.
ZamirskaAReichABerny-MorenoJSalomonJSzepietowskiJC. Vulvar pruritus and burning sensation in women with psoriasis. Acta Derm Venereol. (2008) 88:132–5. 10.2340/00015555-0372
32.
MeeuwisKAPde HulluJAMassugerLFAGvan de KerkhofPCMvan RossumMM. Genital psoriasis: a systematic literature review on this hidden skin disease. Acta Derm Venereol. (2011) 91:5–11. 10.2340/00015555-0988
33.
KapilaSBradfordJFischerG. Vulvar psoriasis in adults and children: a clinical audit of 194 cases and review of the literature. J Low Genit Tract Dis. (2012) 16:364–71. 10.1097/LGT.0b013e31824b9e5e
34.
PowellJJWojnarowskaF. Lichen sclerosus. Lancet. (1999) 353:1777–83. 10.1016/S0140-6736(98)08228-2
35.
LagerstedtMKarvinenKJoki-ErkkiläMHuotari-OravaRSnellmanELaasanenS-L. Childhood lichen sclerosus–a challenge for clinicians. Pediatr Dermatol. (2013) 30:444–50. 10.1111/pde.12109
36.
WallaceHJ. Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soc. (1971) 57:9–30.
37.
PowellJWojnarowskaF. Childhood vulvar lichen sclerosus: an increasingly common problem. J Am Acad Dermatol. (2001) 44:803–6. 10.1067/mjd.2001.113474
38.
GoldsteinATMarinoffSCChristopherKSrodonM. Prevalence of vulvar lichen sclerosus in a general gynecology practice. J Reprod Med. (2005) 50:477–80.
39.
SmithYRHaefnerHK. Vulvar lichen sclerosus. Am J Clin Dermatol. (2004) 5:105–25. 10.2165/00128071-200405020-00005
40.
HartWRNorrisHJHelwigEB. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol. (1975) 45:369–77.
41.
CarlsonJAAmbrosRMalfetanoJRossJGrabowskiRLambPet al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Hum Pathol. (1998) 29:932–48. 10.1016/S0046-8177(98)90198-8
42.
BleekerMCGVisserPJOverbeekLIHvan BeurdenMBerkhofJ. Lichen sclerosus: Incidence and risk of vulvar squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. (2016) 25:1224–30. 10.1158/1055-9965.EPI-16-0019
43.
TerlouASantegoetsLAMvan der MeijdenWIHeijmans-AntonissenCSwagemakersSMAvan der SpekPJet al. An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest Dermatol. (2012) 132:658–66. 10.1038/jid.2011.369
44.
EisenD. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol. (2002) 46:207–14. 10.1067/mjd.2002.120452
45.
EisenD. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. (1999) 88:431–6. 10.1016/S1079-2104(99)70057-0
46.
HandaSSahooB. Childhood lichen planus: a study of 87 cases. Int J Dermatol. (2002) 41:423–7. 10.1046/j.1365-4362.2002.01522.x
47.
GoldsteinATMetzA. Vulvar lichen planus. Clin Obstet Gynecol. (2005) 48:818–23. 10.1097/01.grf.0000179670.98939.b7
48.
DayTWeignerJScurryJ. Classic and hypertrophic vulvar lichen planus. J Low Genit Tract Dis. (2018) 22:387–95. 10.1097/LGT.0000000000000419
49.
ChewAStefanatoCMSavareseINeillSMFentonDALewisFM. Clinical patterns of lichen planopilaris in patients with vulval lichen planus. Br J Dermatol. (2014) 170:218–20. 10.1111/bjd.12609
50.
FruchterRMelnickLPomeranzMK. Lichenoid vulvar disease: a review. Int J Womens Dermatol. (2017) 3:58–64. 10.1016/j.ijwd.2017.02.017
51.
StewartKMA. Clinical care of vulvar pruritus, with emphasis on one common cause, lichen simplex chronicus. Dermatol Clin. (2010) 28:669–80. 10.1016/j.det.2010.08.004
52.
BohlTG. Overview of vulvar pruritus through the life cycle. Clin Obstet Gynecol. (2005) 48:786–807. 10.1097/01.grf.0000179636.64663.e6
53.
MensingHJännerM. Vulvitis plasmacellularis Zoon (author's transl). Z Hautkr. (1981) 56:728–32.
54.
BharatiaPRPradhanAMZawarVP. Plasma cell vulvitis. Indian J Sex Transm Dis AIDS. (2015) 36:185–7. 10.4103/0253-7184.167172
55.
GoldsteinATChristopherKBurrowsLJ. Plasma cell vulvitis: a rare cause of intractable vulvar pruritus. Arch Dermatol. (2005) 141:789–90. 10.1001/archderm.141.6.789
56.
YostJRobinsonMMeehanSA. Fox-Fordyce disease. Dermatol Online J. (2012) 18:28.
57.
GurusamyLJegadeesanMJayakumarS. Fox-Fordyce disease of the vulva. Indian J Sex Transm Dis AIDS. (2016) 37:65–7. 10.4103/0253-7184.180293
58.
MahajanRBangDNagarABilimoriaF. Rare sweat gland tumors of vulva: report of two cases. Indian J Sex Transm Dis AIDS. (2012) 33:124–7. 10.4103/0253-7184.102128
59.
MogielnickiNPSchwartzmanJDElliottJA. Perineal group A streptococcal disease in a pediatric practice. Pediatrics. (2000) 106:276–81. 10.1542/peds.106.2.276
60.
FischerGO. Vulval disease in pre-pubertal girls. Australas J Dermatol. (2001) 42:225–34. 10.1046/j.1440-0960.2001.00526.x
61.
CorselloSSpinilloAOsnengoGPennaCGuaschinoSBeltrameAet al. An epidemiological survey of vulvovaginal candidiasis in Italy. Eur J Obstet Gynecol Reprod Biol. (2003) 110:66–72. 10.1016/S0301-2115(03)00096-4
62.
OkungbowaFIIsikhuemhenOSDedeAPO. The distribution frequency of Candida species in the genitourinary tract among symptomatic individuals in Nigerian cities. Rev Iberoam Micol. (2003) 20:60–3.
63.
BuscemiLArechavalaANegroniR. Study of acute vulvovaginitis in sexually active adult women, with special reference to candidosis, in patients of the Francisco J. Muñiz Infectious Diseases Hospital. Rev Iberoam Micol. (2004) 21:177–81.
64.
FidelPLJrCutrightJSteeleC. Effects of reproductive hormones on experimental vaginal candidiasis. Infect Immun. (2000) 68:651–7. 10.1128/IAI.68.2.651-657.2000
65.
LambertJ. Pruritus in female patients. Biomed Res Int. (2014) 2014:541867. 10.1155/2014/541867
66.
XuJ. Response: Re: Effect of antibiotics on vulvovaginal candidiasis: a metronet study. J Am Board Fam Med. (2009) 22:223. 10.3122/jabfm.2009.02.080258
67.
AhmadAKhanAU. Prevalence of Candida species and potential risk factors for vulvovaginal candidiasis in Aligarh, India. Eur J Obstet Gynecol Reprod Biol. (2009) 144:68–71. 10.1016/j.ejogrb.2008.12.020
68.
FerrazziECarteiGMattarazzoRFiorentinoM. Oestrogen-like effect of tamoxifen on vaginal epithelium. Br Med J. (1977) 1:1351–2. 10.1136/bmj.1.6072.1351-e
69.
SobelJDChaimWLeamanD. Recurrent vulvovaginal candidiasis associated with long-term tamoxifen treatment in postmenopausal women. Obstet Gynecol. (1996) 88:704–6. 10.1016/0029-7844(96)00123-8
70.
LahtiEVuopalaSKauppilaABlancoGRuokonenALaatikainenT. Maturation of vaginal and endometrial epithelium in postmenopausal breast cancer patients receiving long-term tamoxifen. Gynecol Oncol. (1994) 55:410–4. 10.1006/gyno.1994.1314
71.
SmeekensSPvan de VeerdonkFLKullbergBJNeteaMG. Genetic susceptibility to Candida infections. EMBO Mol Med. (2013) 5:805–13. 10.1002/emmm.201201678
72.
SobelJD. Vulvovaginal candidosis. Lancet. (2007) 369:1961–71. 10.1016/S0140-6736(07)60917-9
73.
SiegfriedECFrasierLD. Anogenital skin diseases of childhood. Pediatr Ann. (1997) 26:321–31. 10.3928/0090-4481-19970501-11
74.
BignellC. Lice and scabies. Medicine. (2014) 42:382–4. 10.1016/j.mpmed.2014.04.008
75.
IngramJT. Tinea of vulva. BMJ. (1955) 2:1500. 10.1136/bmj.2.4954.1500
76.
RogersLJCuelloMA. Cancer of the vulva. Int J Gynaecol Obstet. (2018) 143(Suppl. 2):4–13. 10.1002/ijgo.12609
77.
KehilaMHarabiSMhiriRTouhamiOAboudaHSKhlifiAet al. Vulvar cancer in Tunisia: epidemiological and clinicopathological features multicentric study. J Egypt Natl Canc Inst. (2017) 29:95–8. 10.1016/j.jnci.2017.02.001
78.
KingstonA. Vulval disease in the postmenopausal patient: a guide to current management. Menopause Int. (2010) 16:117–20. 10.1258/mi.2010.010031
79.
FanningJLambertHCLHaleTMMorrisPCSchuerchC. Paget's disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget's disease, and recurrence after surgical excision. Am J Obstet Gynecol. (1999) 180:24–7. 10.1016/S0002-9378(99)70143-2
80.
TebesSCardosiRHoffmanM. Paget's disease of the vulva. Am J Obstet Gynecol. (2002) 187:281–3. 10.1067/mob.2002.125700
81.
HoffmannPE. Malignancies of the vulva. Am J Obstet Gynecol. (1937) 33:60–7. 10.1016/S0002-9378(15)32743-5
82.
NganHYCheungANLiuSSYipPSTsaoSW. Abnormal expression or mutation of TP53 and HPV in vulvar cancer. Eur J Cancer. (1999) 35:481–4. 10.1016/S0959-8049(98)00407-9
83.
HellerDS. Benign tumors and tumor-like lesions of the vulva. Clin Obstet Gynecol. (2015) 58:526–35. 10.1097/GRF.0000000000000133
84.
El-KhouryJRenaldM-HPlantierFAvrilM-FMoyal-BarraccoM. Vulvar hidradenoma papilliferum (HP) is located on the sites of mammary-like anogenital glands (MLAGs): analysis of the photographs of 52 tumors. J Am Acad Dermatol. (2016) 75:380–4. 10.1016/j.jaad.2016.01.034
85.
BakerGMSelimMAHoangMP. Vulvar adnexal lesions: a 32-year, single-institution review from Massachusetts General Hospital. Arch Pathol Lab Med. (2013) 137:1237–46. 10.5858/arpa.2012-0434-OA
86.
KambilSMBhatRMD'SouzaDC. Hidradenoma papilliferum of the vulva. Indian Dermatol Online J. (2014) 5:523–4. 10.4103/2229-5178.142541
87.
DabralRJetlyDGoelD. Hidradenoma papilliferum of the vulva with extensive squamous metaplasia mimicking malignancy: rare entity with diagnostic challenge. Oncol J India. (2019) 3:38. 10.4103/oji.oji_23_19
88.
CorkMJDanbySGVasilopoulosYHadgraftJLaneMEMoustafaMet al. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. (2009) 129:1892–908. 10.1038/jid.2009.133
89.
PotenzieriCUndemBJ. Basic mechanisms of itch. Clin Exp Allergy. (2012) 42:8–19. 10.1111/j.1365-2222.2011.03791.x
90.
ElsnerPMaibachHI. The effect of prolonged drying on transepidermal water loss, capacitance and pH of human vulvar and forearm skin. Acta Derm Venereol. (1990) 70:105–9.
91.
BritzMBMaibachHI. Human labia majora skin: transepidermal water loss in vivo. Acta Derm Venereol Suppl. (1979) 59:23–5.
92.
BritzMBMaibachHI. Human cutaneous vulvar reactivity to irritants. Contact Dermat. (1979) 5:375–7. 10.1111/j.1600-0536.1979.tb04908.x
93.
ElsnerPWilhelmDMaibachHI. Effect of low-concentration sodium lauryl sulfate on human vulvar and forearm skin. Age-related differences. J Reprod Med. (1991) 36:77–81.
94.
Pichardo-GeisingerR. Atopic and contact dermatitis of the vulva. Obstet Gynecol Clin North Am. (2017) 44:371–8. 10.1016/j.ogc.2017.05.003
95.
YongAACaoTTanVYosipovitchGTeyHL. Skin physiology in pruritus of advanced ageing. J Eur Acad Dermatol Venereol. (2016) 30:549–50. 10.1111/jdv.12948
96.
LiuBTaiYAchantaSKaelbererMMCaceresAIShaoXet al. IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy. Proc Natl Acad Sci U S A. (2016) 113:E7572–9. 10.1073/pnas.1606608113
97.
WilsonSRThéLBatiaLMBeattieKKatibahGEMcClainSPet al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. (2013) 155:285–95. 10.1016/j.cell.2013.08.057
98.
ReddyVBSunSAzimiEElmariahSBDongXLernerEA. Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs. Nat Commun. (2015) 6:7864. 10.1038/ncomms8864
99.
HägermarkO. Studies on experimental itch induced by kallikrein and bradykinin. Acta Derm Venereol. (1974) 54:397–400.
100.
AkiyamaTLernerEACarstensE. Protease-activated receptors and itch. Handb Exp Pharmacol. (2015) 226:219–35. 10.1007/978-3-662-44605-8_13
101.
YosipovitchGGreavesMWSchmelzM. Itch. Lancet. (2003) 361:690–4. 10.1016/S0140-6736(03)12570-6
102.
ÜckertSSonnenbergJEAlbrechtKKuczykMAHedlundP. Expression and distribution of the transient receptor potential cationic channel ankyrin 1 (TRPA1) in the human vagina. Int J Impot Res. (2015) 27:16–9. 10.1038/ijir.2014.23
103.
PierceANZhangZFuentesIMWangRRyalsJMChristiansonJA. Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice. Pain. (2015) 156:2021–31. 10.1097/j.pain.0000000000000264
104.
TympanidisPTerenghiGDowdP. Increased innervation of the vulval vestibule in patients with vulvodynia. Br J Dermatol. (2003) 148:1021–7. 10.1046/j.1365-2133.2003.05308.x
105.
TympanidisPCasulaMAYiangouYTerenghiGDowdPAnandP. Increased vanilloid receptor VR1 innervation in vulvodynia. Eur J Pain. (2004) 8:129–33. 10.1016/S1090-3801(03)00085-5
106.
PhillipsNABrownCFosterDBachourCRawlinsonLWanJet al. Presenting symptoms among premenopausal and postmenopausal women with vulvodynia: a case series. Menopause. (2015) 22:1296–300. 10.1097/GME.0000000000000526
107.
StumpfAStänderS. Neuropathic itch: diagnosis and management. Dermatol Ther. (2013) 26:104–9. 10.1111/dth.12028
108.
CohenADVanderTMedvendovskyEBitonANaimerSShalevRet al. Neuropathic scrotal pruritus: anogenital pruritus is a symptom of lumbosacral radiculopathy. J Am Acad Dermatol. (2005) 52:61–6. 10.1016/j.jaad.2004.04.039
109.
OaklanderALRissmillerJG. Postherpetic neuralgia after shingles: an under-recognized cause of chronic vulvar pain. Obstet Gynecol. (2002) 99:625–8. 10.1016/S0029-7844(01)01663-5
110.
OaklanderAL. The pathology of postherpetic neuralgia and postherpetic itch. In: Herpes Zoster: Postherpetic Neuralgia and Other Complications. Cham: Springer International Publishing. (2017). p. 141–56. 10.1007/978-3-319-44348-5_12
111.
OaklanderALBowsherDGalerBHaanpääMJensenMP. Herpes zoster itch: preliminary epidemiologic data. J Pain. (2003) 4:338–43. 10.1016/S1526-5900(03)00637-0
112.
FarageMMaibachH. Lifetime changes in the vulva and vagina. Arch Gynecol Obstet. (2006) 273:195–202. 10.1007/s00404-005-0079-x
113.
HammerschlagMRAlpertSRosnerIThurstonPSemineDMcCombDet al. Microbiology of the vagina in children: normal and potentially pathogenic organisms. Pediatrics. (1978) 62:57–62.
114.
BrabinLRobertsSAFairbrotherEMandalDHigginsSPChandiokSet al. Factors affecting vaginal pH levels among female adolescents attending genitourinary medicine clinics. Sex Transm Infect. (2005) 81:483–7. 10.1136/sti.2005.014621
115.
PausRSchmelzMBÃróTSteinhoffM. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest. (2006) 116:1174–86. 10.1172/JCI28553
116.
SteinhoffMBuddenkotteJShpacovitchVRattenhollAMoormannCVergnolleNet al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev. (2005) 26:1–43. 10.1210/er.2003-0025
117.
StefanssonKBrattsandMRoostermanDKempkesCBochevaGSteinhoffMet al. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol. (2008) 128:18–25. 10.1038/sj.jid.5700965
118.
KomatsuNSaijohKKukCLiuACKhanSShirasakiFet al. Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. Exp Dermatol. (2007) 16:513–9. 10.1111/j.1600-0625.2007.00562.x
119.
KomatsuNSaijohKKukCShirasakiFTakeharaKDiamandisEP. Aberrant human tissue kallikrein levels in the stratum corneum and serum of patients with psoriasis: dependence on phenotype, severity and therapy. Br J Dermatol. (2007) 156:875–83. 10.1111/j.1365-2133.2006.07743.x
120.
SteinhoffMVergnolleNYoungSHTognettoMAmadesiSEnnesHSet al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. (2000) 6:151–8. 10.1038/72247
121.
BrainSD. New feelings about the role of sensory nerves in inflammation. Nat Med. (2000) 6:134–5. 10.1038/72218
122.
KempkesCBuddenkotteJCevikbasFBuhlTSteinhoffM. 11 role of PAR-2 in neuroimmune communication and itch. In: Itch: Mechanisms and Treatment. Davis, CA: CRC Press (2014). p. 193.
123.
SteinhoffMCorveraCUThomaMSKongWMcAlpineBECaugheyGHet al. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol. (1999) 8:282–94. 10.1111/j.1600-0625.1999.tb00383.x
124.
LeeSEJeongSKLeeSH. Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis. Yonsei Med J. (2010) 51:808–22. 10.3349/ymj.2010.51.6.808
125.
Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. (2012) 486:207–14. 10.1038/nature11234
126.
AmabebeEAnumbaDOC. The vaginal microenvironment: the physiologic role of lactobacilli. Front Med. (2018) 5:181. 10.3389/fmed.2018.00181
127.
MacIntyreDAChandiramaniMLeeYSKindingerLSmithAAngelopoulosNet al. The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci Rep. (2015) 5:8988. 10.1038/srep08988
128.
GriceEASegreJA. The skin microbiome. Nat Rev Microbiol. (2011) 9:244–53. 10.1038/nrmicro2537
129.
IwaseTUeharaYShinjiHTajimaASeoHTakadaKet al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature. (2010) 465:346–9. 10.1038/nature09074
130.
LaiYDi NardoANakatsujiTLeichtleAYangYCogenALet al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med. (2009) 15:1377–82. 10.1038/nm.2062
131.
RoanFObata-NinomiyaKZieglerSF. Epithelial cell-derived cytokines: more than just signaling the alarm. J Clin Invest. (2019) 129:1441–51. 10.1172/JCI124606
132.
Sung KimHYosipovitchG. The skin microbiota and itch: is there a link?J Clin Aesthet Dermatol. (2020) 13:39–46. 10.3390/jcm9041190
133.
CorbièreALosteAGaudenzioN. MRGPRX2 sensing of cationic compounds-A bridge between nociception and skin diseases?Exp Dermatol. (2021) 30:193–200. 10.1111/exd.14222
134.
GambichlerTSkryganMTiggesCKobusSGläserRKreuterA. Significant upregulation of antimicrobial peptides and proteins in lichen sclerosus. Br J Dermatol. (2009) 161:1136–42. 10.1111/j.1365-2133.2009.09273.x
135.
ChiuIMHeestersBAGhasemlouNVon HehnCAZhaoFTranJet al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature. (2013) 501:52–7. 10.1038/nature12479
136.
Ochoa-CortesFRamos-LomasTMiranda-MoralesMSpreadburyIIbeakanmaCBarajas-LopezCet al. Bacterial cell products signal to mouse colonic nociceptive dorsal root ganglia neurons. Am J Physiol Gastrointest Liver Physiol. (2010) 299:G723–32. 10.1152/ajpgi.00494.2009
137.
DiogenesAFerrazCCRAkopianANHenryMAHargreavesKM. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res. (2011) 90:759–64. 10.1177/0022034511400225
138.
TaylorJS. Allergic contact dermatitis from doxepin cream. Arch Dermatol. (1996) 132:515. 10.1001/archderm.1996.03890290049006
139.
BonnelRALa GrenadeLKarwoskiCBBeitzJG. Allergic contact dermatitis from topical doxepin: food and drug administration's postmarketing surveillance experience. J Am Acad Dermatol. (2003) 48:294–6. 10.1067/mjd.2003.46
140.
SzmulowiczUM. Pruritus Ani. In: Zutshi M, editor. Anorectal Disease: Contemporary Management. Cham: Springer International Publishing. (2016). p. 153–87. 10.1007/978-3-319-23147-1_7
141.
Berth-JonesJTakwaleATanEBarclayGAgarwalSAhmedIet al. Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol. (2002) 147:324–30. 10.1046/j.1365-2133.2002.04989.x
142.
GoujonCNicolasJFNosbaumA. Methotrexate in atopic eczema. Comments to: Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol. (2019) 33:e154–5. 10.1111/jdv.15386
143.
Grundmann-KollmannMPoddaMOchsendorfFBoehnckeWHKaufmannRZollnerTM. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol. (2001) 137:870–3. 10.1001/pubs.ArchDermatol.-ISSN-0003-987x-137-7-dst10044
144.
JacobiAAntoniCMangerBSchulerGHertlM. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. (2005) 52:522–6. 10.1016/j.jaad.2004.11.022
145.
ReefSELevineWCMcNeilMMFisher-HochSHolmbergSDDuerrAet al. Treatment options for vulvovaginal candidiasis, 1993. Clin Infect Dis. (1995) 20(Suppl. 1):S80–90. 10.1093/clinids/20.Supplement_1.S80
146.
WendelKRompaloA. Scabies and pediculosis pubis: an update of treatment regimens and general review. Clin Infect Dis. (2002) 35:S146–51. 10.1086/342102
147.
PaekSCMerrittDFMallorySB. Pruritus vulvae in prepubertal children. J Am Acad Dermatol. (2001) 44:795–802. 10.1067/mjd.2001.112578
148.
FishmanSMCanerisOAStojanovicMPBorsookD. Intravenous lidocaine for treatment-resistant pruritus. Am J Med. (1997) 102:584–5. 10.1016/S0002-9343(97)00057-0
149.
BuellerHABernhardJDDubroffLM. Gabapentin treatment for brachioradial pruritus. J Eur Acad Dermatol Venereol. (1999) 13:227–8. 10.1111/j.1468-3083.1999.tb00890.x
150.
TrivediMKWoodruffCMKornikRBottoN. Patch testing in vulvar allergic contact dermatitis. Dermatitis. (2018) 29:95–6. 10.1097/DER.0000000000000345
151.
EhlersAStangierUGielerU. Treatment of atopic dermatitis: a comparison of psychological and dermatological approaches to relapse prevention. J Consult Clin Psychol. (1995) 63:624–35. 10.1037/0022-006X.63.4.624
152.
ZhongCSElmariahSB. Phototherapy for itch. Dermatol Clin. (2020) 38:145–55. 10.1016/j.det.2019.08.008
153.
RivardJLimHW. Ultraviolet phototherapy for pruritus. Dermatol Ther. (2005) 18:344–54. 10.1111/j.1529-8019.2005.00032.x
154.
von KobyletzkiGPieckCHoffmannKFreitagMAltmeyerP. Medium-dose UVA1 cold-light phototherapy in the treatment of severe atopic dermatitis. J Am Acad Dermatol. (1999) 41:931–7. 10.1016/S0190-9622(99)70249-5
155.
ReynoldsNJFranklinVGrayJCDiffeyBLFarrPM. Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet. (2001) 357:2012–6. 10.1016/S0140-6736(00)05114-X
156.
NarbuttJOlejniczakISobolewska-SztychnyDSysa-JedrzejowskaASłowik-KwiatkowskaIHawroTet al. Narrow band ultraviolet B irradiations cause alteration in interleukin-31 serum level in psoriatic patients. Arch Derm Res. (2013) 305:191–5. 10.1007/s00403-012-1293-6
Summary
Keywords
vulva, pruritus, itch, neurogenic itch, barrier function, neuropathic itch
Citation
Raef HS and Elmariah SB (2021) Vulvar Pruritus: A Review of Clinical Associations, Pathophysiology and Therapeutic Management. Front. Med. 8:649402. doi: 10.3389/fmed.2021.649402
Received
04 January 2021
Accepted
12 March 2021
Published
07 April 2021
Volume
8 - 2021
Edited by
Sonja Ständer, University Hospital Münster, Germany
Reviewed by
Joanna Wallengren, Lund University, Sweden; Asit Kumar Mittal, Ravindra Nath Tagore Medical College, India; Elke Weisshaar, Heidelberg University Hospital, Germany
Updates
Copyright
© 2021 Raef and Elmariah.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Haya S. Raef haya.raef@tufts.eduSarina B. Elmariah sbelmariah@mgh.harvard.edu
This article was submitted to Dermatology, a section of the journal Frontiers in Medicine
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.