In an adult woman's reproductive years, the bacterial flora of the healthy vagina contains numerous microorganisms, including aerobic and anaerobic gram-positive and gram-negative bacteria. Lactobacillus and Corynebacterium predominate over other bacteria such as Streptococcus, Bacteroides, Staphylococcus, and Peptostreptococcus.
Lactobacillus and Corynebacterium produce lactic and acetic acid from glycogen, thus maintaining the low vaginal pH. Additional bacteria are kept in check by the acid-producing bacteria and are rarely pathogenic, but they may become pathogenic if the environmental balance is affected.
Vaginal pH may increase with age, decreases in estrogen, menstrual cycle phase, sexual activity, contraceptive choice, pregnancy, the presence of necrotic tissue or foreign bodies, or the use of hygienic products or antibiotics. [5]
Vulvovaginal candidiasis
Vulvovaginal candidiasis can be an acute, chronic, recurrent, or persistent condition that can involve the vulva, vagina, and adjacent crural areas. The specific causative agent belongs to the genus Candida. These organisms are found in almost all humans and many animals. An estimated 10-50% of reproductive-aged American women are considered opportunistic carriers.
The species C albicans is identified approximately 85-90% of the time. However, an increased frequency of other Candida species, such as C glabrata, C tropicalis, and C krusei, has been reported. The emergence of these other Candida species may possibly be due to widespread use of over-the-counter drugs, long-term use of suppressive azoles, and the use of frequent short courses of antifungal drugs.
Pregnancy
Any host factor that affects the vaginal environment or vaginal secretions can play a role in the initiation of Candida vulvovaginitis. Pregnancy is one of the most common predisposing factors. Studies have demonstrated that up to one third of pregnant women worldwide on any day can be affected. The high levels of reproductive hormones and an increase in the vaginal environment’s glycogen content create a favorable environment for Candida species, providing an abundant source of carbon for candidal growth, germination, and adherence.
Furthermore, the acidity of the pregnant vaginal flora can suppress the growth of other microorganisms that are naturally inhibitory to Candida. Although the initial attachment of the organism occurs more readily at high pH values (6-7), the germ tube formation and the development of mycelia are favored by a low vaginal pH (< 5).
Contraception
Older studies of women using high-dose estrogens in oral contraceptives found an increase in vaginal colonization by Candida. The mechanism is believed to be similar to that found in pregnancy. However, newer oral contraceptives with a lower estrogen dose do not seem to predispose the patient to vulvovaginal candidiasis.
Other causes
Disorders associated with an altered immune response, such as acquired immunodeficiency syndrome (AIDS) and diabetes mellitus, also predispose women to Candida vulvovaginitis.
Antimicrobials are thought to predispose a patient to Candida by reducing the number of protective resident vaginal bacteria. The most common offenders are broad-spectrum agents such as tetracycline, cephalosporins, and ampicillin-like agents. Tight-fitting undergarments are another potential factor in the development of vulvovaginal candidiasis.
A study by Horowitz et al demonstrated Candida species in ejaculate fluid of partners of patients with recurrent Candida infections, but they suggested that the carrier rate may be low. [6] Traditionally, vulvovaginal candidiasis is not considered a sexually transmitted infection, because it occurs in celibate women, and Candida itself is considered part of the normal vaginal flora.
Recurrent vulvovaginal candidiasis
Although most women with vulvovaginal candidiasis respond quickly to treatment, the recurrent form of the disease, defined as 4 or more episodes of infection per year, may occur (albeit in less than 5% of healthy women). Predisposing factors for recurrent infection are apparent in only a minority of women; they include poorly controlled diabetes and immunosuppressive therapy.
Other factors that may predispose to recurrent infection include abnormalities in local vaginal mucosal immunity and genetic susceptibility. Studies have found that women with recurrent infections have a higher frequency of certain Lewis blood group antigens and specific gene polymorphisms compared with controls.
Recurrent vulvovaginal candidiasis has also been associated with a decreased in vivo concentration of mannose binding lectin (MBL) and an increased concentration of interleukin-4 (IL-4). Studies have shown that the prevalence of a variant MLB gene is higher in women with recurrent vulvovaginal candidiasis than in controls without candidiasis. Furthermore, IL-4 blocks the anti-Candida response mediated by macrophages; thus, elevation of IL-4 levels results in the inhibition of local defense mechanisms. [7, 8]
The role of sexual transmission in recurrent infection remains unresolved. Most studies do not support treatment of sexual partners. [9] Horowitz et al reported on 54 women with recurrent Candida vaginitis and found no significant difference in the rate of relapse between women with untreated or treated partners. [6]
Recurrences may be caused by other species of Candida that are not equally susceptible to the usual first-line treatments. In vitro studies have shown that imidazole antifungal agents, such as miconazole and clotrimazole, are not as effective against non–C albicans fungi. C tropicalis and C glabrata are 10 times less sensitive to miconazole than is C albicans. Appropriate fungal cultures may be taken to identify the species. Treatment entails longer courses of antimycotic therapy (10-14 days), regardless of the route of administration.
Genitourinary syndrome of menopause
Extremely low estrogen production, as found after menopause or bilateral oophorectomy, can lead to atrophy of the vaginal and vulvar epithelium. Vulvovaginal atrophy is considered a natural process after estrogen withdrawal. Although menopause is the leading cause of decreased levels of circulating estrogen, atrophy of the vagina can occur in nonmenopausal women due to diminished ovarian estrogen production, as can result from cancer treatments, such as radiation therapy and chemotherapy, and immunologic disorders.
Furthermore, in postpartum women, the decline in estrogen levels in conjunction with the loss of placental estrogen and the antagonistic action of prolactin on estrogen production during lactation can lead to vulvovaginal atrophy. [10]
Among its many effects, estrogen helps to maintain the collagen content of the epithelium and thus affects its thickness and elasticity. It also helps to maintain acid mucopolysaccharides and hyaluronic acid, which keep epithelial surfaces moist. During the reproductive years, estrogen stimulation is responsible for maintenance of a well-epithelialized vaginal vault. It causes the nonkeratinized stratified squamous epithelium of the vagina to be thick, rugated, and rich in glycogen. Glycogen is necessary for rapid multiplication and maintenance of lactobacilli.
Menopause
During the perimenopausal period, estrogen secretion, primarily estradiol, remains at approximately 120 ng/L. After menopause, it decreases to approximately 18 ng/L. The reduction of endogenous estrogen causes thinning of the epithelium and a diminished glycogen content. The lack of glycogen contributes to a reduction in lactic acid production and an increase in vaginal pH, thus leading to the overgrowth of nonacidophilic species and the disappearance of Lactobacillus. In some patients, this new flora may include bacteria that can incite a superficial infection in denuded regions and alter vaginal secretions. [11]
In addition, during estrogen withdrawal, the papillae of the vagina flatten and the rugae nearly disappear, leaving the vagina relatively smooth. The mucosa becomes progressively thinner and eventually may become only a few cell layers thick. A moderately thick layer of intermediate cells may be present in some areas, with only a row of basal cells in others. Eventually, the vagina becomes denuded of epithelium.
Provoked vestibulodynia
The classic definition of vulvar vestibulitis (previous term for provoked vestibulodynia), according to Freidrich's criteria, includes the following signs and symptoms confined to the vulvar vestibule:
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Severe pain upon touching the vestibule or attempted vaginal entry
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Tenderness to pressure localized within the vulvar vestibule
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Physical findings confined to vestibular erythema of various degrees
The vestibule consists of nonpigmented and nonkeratinized squamous epithelium devoid of skin. It contains mucus-secreting minor vestibular glands, ductal orifices of the Bartholin glands, Skene glands, and the urethral meatus. Associated factors of vestibulodynia include hormonal, musclar, nerve-related, and inflammatory causes.
Histology
Initially, provoked vestibulodynia was considered a chronic local inflammatory condition because of vulvar biopsies that showed infiltration by inflammatory cells. However, a similar inflammatory infiltrate was identified in the vestibule of women without provoked vestibulodynia. Nonetheless, studies suggest that inflammation may have a contributing role (see Neurologic pathophysiology below). [12]
Infectious etiologies
Provoked vestibulodynia was not widely recognized until Woodruff and Parmley reported on it in the 1980s. [13] They thought that the etiology was an infection of the vestibular glands that was best treated by perineoplasty.
Marinoff and Pyka proposed that Candida may be a causative organism in provoked vestibulodynia; however, the presence of yeast in patients with the condition has not been confirmed by other reports.
More recent studies have investigated the role of human papillomavirus (HPV) infection; however, the evidence has been controversial. [14] Turner and Marinoff [15] reported a 100% rate of HPV positivity in vulvar biopsies in 7 patients with provoked vestibulodynia, while Bergeron reported negative viral findings in all 11 of his biopsies. Further studies are needed to elucidate the relationship, if any, between HPV and provoked vestibulodynia.
Noninfectious etiologies
Possible noninfectious causes of provoked vestibulodynia include the following:
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Vulvovaginal candidiasis therapy - Some authors believe that the disease may result from allergic sensitization within the vulvar vestibule to several types of topical medication for vulvovaginal candidiasis
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HPV therapy - Treatments for clinical and subclinical HPV, [16] such as cryosurgery, trichloroacetic acid, podophyllin, and laser treatment, have been implicated in the development of provoked vestibulodynia
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5-fluorouracil cream - Several cases of provoked vestibulodynia have been reported after the use of this agent, which is administered for the treatment of actinic keratoses and superficial basal cell carcinoma
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Chemical irritants - An association between such agents, including those found in feminine hygiene products, and provoked vestibulodynia has been investigated
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Alkaline vaginal pH - This has been demonstrated to cause irritation to the vestibule; agents that alter the vaginal pH can lead to the overgrowth of anaerobic and/or the disappearance of normal flora (ie, Lactobacillus); hypotheses suggest that the constant bathing of the vestibule by an alkaline vaginal discharge may lead to chronic irritation and inflammation
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Other - Some authors have associated provoked vestibulodynia with a history of sexual abuse, elective abortions, severe marital conflicts, depression, and anxiety
Neurologic pathophysiology
Studies have focused on specific pain receptors found in the vulvar tissue. As a brief overview, the sensory innervation of the inferior portion of the vulva is primarily from the branches of the pudendal nerve. The ilioinguinal and branches of the genitofemoral nerve innervate the superior portion of the vulva. These nerve fibers are of 2 types: (1) those responsible for touch and (2) those responsible for nociception (perception of noxious stimuli).
The mechanism hypothesized is that the nociception fibers are innervated first instead of the touch fibers. This is followed by a prolonged innervational response of the nociception fibers, leading to an abnormal neurologic response from the dorsal horn of the medulla.
Westrom and Willen tested this theory by obtaining vulvar biopsies of 47 women with clinical vestibulitis. In 44 specimens, they noted not only regions of marked increase of vestibular nerve formation , but also a significant correlation between inflammation and nerve-bundle density. The authors concluded that a chronic inflammatory reaction in the vestibule might lead to proliferation of nerve fibers. Thus, treatment entailed surgical removal of these nerve fibers. [17] Later studies have confirmed the increased vestibular nerve fiber density first reported by Westrom and Willen and have suggested that immune activation enhances epithelial nerve growth. [12, 18]
Contact dermatitis
The vulvar skin is a frequent site of contact dermatitis; the cutaneous response may be either allergic or irritant induced. An allergic reaction implies previous exposure to an allergen and sensitization. It is a cell-mediated (type IV) immunologic response that can occur in sensitized individuals.
Irritant-induced contact dermatitis can be acute or chronic. It may occur from acute exposure to a potent irritant or upon repeated exposure to a weak irritant. Irritants that can cause contact dermatitis include the following:
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Moisture
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Urine
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Vaginal discharge
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Topical medications
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Anticandidal agents
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Latex
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Spermicidal agents
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Cosmetics
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Douching
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Fragrances
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Cleansing products
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Underwear
