Vulvovaginitis

Vulvovaginitis, a general term referring to many types of vaginal infection, is the most common gynecologic condition seen by practitioners rendering primary care to women. Discharge, burning, and pruritus are the most common symptoms, accompanied by signs of vulvar irritation, such as erythema and excoriation of the vulvar skin. (See Presentation.)

Traditionally, the 3 classic entities of vaginitis include bacterial vaginosis, Trichomonas infection, and candidiasis. This article, however, focuses on disorders that affect the vulvar region, including the following (see the image below):

• Vulvovaginal candidiasis

• Atrophic vaginitis

• Vulvar vestibulitis

• Contact dermatitis

  Candida albicans photomicrograph. Courtesy of Centers for Disease Control and Prevention (CDC).

The differential diagnosis for women with symptoms of vulvovaginitis is complex. Discharge, burning, and pruritus usually are the presenting symptoms, with signs of vulvar irritation that may include erythema and excoriation of the vulvar skin. Primary or secondary infections, skin irritants, or contact dermatitis may produce vulvar irritation. Irritation from bodily fluids such as urine and normal vaginal secretions may cause symptoms when the environment is kept moist, as with tight-fitting or occlusive clothing. (See Pathophysiology and Etiology, Presentation, and Workup.)

Because each disorder produces a similar clinical presentation, a careful history must be taken, an examination must be performed, and the vaginal discharge should be examined. Along with medical treatment, the patient must be encouraged to avoid etiologic agents and to make necessary changes in her habits. (See Treatment and Medication.)

Patient education

For patient education information, see the Pregnancy Center and the Women's Health Center, as well as Vaginal Infections (Vaginitis), Candidiasis (Yeast Infection), Vaginal Yeast Infection Treatment, Female Sexual Problems, and Trichomoniasis.

The vulva, the external genitalia of the female, includes the labia majora and minora, the clitoris, and the vestibule of the vagina. The skin of the vulva is sensitive to the vaginal environment and hormonal, metabolic, and allergic influences. It is composed of stratified squamous epithelium that contains hair follicles, sebaceous sweat glands, and apocrine glands.

During the reproductive years of a healthy woman's life, the vagina maintains a moist environment that is in constant fluctuation. The secretion of an alkaline transudate from the vaginal epithelium and cervical glands maintains this moist environment with a pH ranging from 3.8-4.5. In addition, the vagina and its microflora form a unique, balanced environment that can change under pressure from external stimuli but returns to normal with removal of the stimuli. It can vary in degree during sexual activity, pregnancy, and the menstrual cycle.

The vaginal epithelium consists of 3 cell layers; ie, superficial, intermediate, and basal. The cells in these layers are capable of storing glycogen under the influence of estrogen. Glycogen is available in the fully mature cells in the superficial layer of the epithelium. With elevated levels of either exogenous or endogenous estrogen, all levels of the epithelium thicken as a result of glycogen storage. With diminishing levels of estrogen, the layers become thin and atrophic.

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, menstrual cycle phase, sexual activity, contraceptive choice, pregnancy, the presence of necrotic tissue or foreign bodies, or the use of hygienic products or antibiotics.[3]

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.[4] Traditionally, vulvovaginal candidiasis is not considered a sexually transmitted disease, 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.[5, 6, 7, 8]

The role of sexual transmission in recurrent infection remains unresolved. Although controversial, 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.[4]

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.

Atrophic vaginitis

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 atrophy.

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.[10]

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.

Vulvar vestibulitis

The classic definition of vulvar vestibulitis, according to Freidrich's criteria, includes the following signs and symptoms confined to the vulvar vestibule:

• Severe pain upon touching the vestibule or attempted vaginal entry

• Tenderness to pressure localized within the vulvar vestibule

• 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. It is within this region that the inflammatory entity vulvar vestibulitis arises. While many theories have been proposed, the etiology of this condition remains unknown.

Histology

Histopathologic studies have not been helpful in determining etiology, demonstrating a nonspecific inflammation of the vestibular region affecting mostly the superficial stroma and occasionally the epithelium. In 1988, Pyka et al studied surgically excised specimens of the vulvar vestibule from 41 patients with vulvar vestibulitis. Pyka identified it in 66% of the specimens' minor vestibular glands. All of these glands demonstrated some degree of squamous metaplasia forming vestibular clefts.[11]

Infectious etiologies

Vulvar vestibulitis was not widely recognized until Woodruff and Parmley reported on it in the 1980s.[12] 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 vulvar vestibulitis; 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.[13] Turner and Marinoff[14] reported a 100% rate of HPV positivity in vulvar biopsies in 7 patients with vestibulitis, 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 vulvar vestibulitis.

Noninfectious etiologies

Possible noninfectious causes of vulvar vestibulitis include the following:

• 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

• HPV therapy - Treatments for clinical and subclinical HPV,[15] such as cryosurgery, trichloroacetic acid, podophyllin, and laser treatment, have been implicated in the development of vulvar vestibulitis

• 5-fluorouracil cream - Several cases of vulvar vestibulitis have been reported after the use of this agent, which is administered for the treatment of actinic keratoses and superficial basal cell carcinoma

• Chemical irritants - An association between such agents, including those found in feminine hygiene products, and vulvar vestibulitis has been investigated

• 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

• Other - Some authors have associated vulvar vestibulitis with a history of sexual abuse, elective abortions, severe marital conflicts, depression, and anxiety

Neurologic pathophysiology

Studies have begun to focus 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 that not only were regions of marked increase of vestibular nerve formation present, but a significant correlation was found 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 had entailed surgical removal of these nerve fibers.[16]

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:

• Moisture

• Urine

• Vaginal discharge

• Topical medications

• Anticandidal agents

• Latex

• Spermicidal agents

• Cosmetics

• Douching

• Fragrances

• Cleansing products

• Underwear

Occurrence in the United States

Vulvovaginal candidiasis

At some point in their lifetime, nearly 75% of all women experience an attack of vulvovaginal candidiasis, with approximately 50% of college-aged women having an episode. About half of the women who develop the condition have more than 1 episode, and a few have frequent relapses.[17, 18] Patients with recurrent or severe vulvovaginal candidiasis warrant a screening test for diabetes mellitus.

Atrophic candidiasis

After menopause, most women experience some vaginal atrophy as estrogen levels fall. The incidence of atrophic vaginitis depends on how it is defined. Vulvovaginitis related to infection is much less common after menopause. Desquamative inflammatory vaginitis, an exception, has an unknown etiology, but a Gram stain of culture often reveals streptococci. This is treated with intravaginal clindamycin cream or a topical or intravaginal steroid.[19]

International occurrence

An international study by Foxman et al on the rate of vulvovaginal candidiasis in Western nations found a high incidence of the disease in these countries. The investigators examined rates in the United States and 5 European nations, using surveys from about 6000 women aged 16 years and older. They determined that among the 6 countries, rates of vulvovaginal candidiasis ranged from 29-49%. It was also found that the recurrent form of the disease developed in more than one fifth of the reported cases.[20]

Age-related demographics

Candida species infections are most common during childbearing years. Atrophic vaginitis may develop several years after menopause. Most women with vaginal atrophy do not develop symptomatic atrophic vaginitis.

Vulvovaginal candidiasis

Most women with vulvovaginal candidiasis usually respond quickly to treatment. Despite therapy, however, recurrent vulvovaginal candidiasis, defined as 4 or more episodes of infection per year, can occur, although in less than 5% of healthy women. Predisposing factors for recurrent infection are apparent in only a minority of women, and 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 than do controls.

Atrophic vaginitis

Accumulating evidence indicates that the vaginal symptoms readily respond to estrogen treatment. With treatment, mucosal thickening with glandular function can be maintained well into the postmenopausal period.

Vulvar vestibulitis

Generally, no specific cure is available, but spontaneous resolution has been reported; thus, treatment should focus on alleviation of symptoms.

Vulvovaginal candidiasis

Acute vulvovaginal candidiasis

In acute vulvovaginal candidiasis, vulvar pruritus and burning are the main symptoms. Patients commonly complain of both symptoms after intercourse or upon urination. Dyspareunia may develop and become severe enough to lead to intolerance of intercourse.

Physical findings include erythema and edema of the vestibule and of the labia majora and minora. The rash may extend to the thighs and perineum. Thrush patches are usually found loosely adherent to the vulva. A thick, white, curdlike vaginal discharge is usually present.[21, 22, 23, 24]

Chronic vulvovaginal candidiasis

The clinical picture of chronic, persistent vulvovaginal candidiasis differs in that it includes marked edema and lichenification of the vulva with poorly defined margins. Often, a grayish sheen made up of epithelial cells and organism covers the area. Symptoms include severe pruritus, burning, irritation, and pain. Patients with chronic candidiasis are usually older and obese and often have long-standing diabetes mellitus.[25]

Atrophic vaginitis

Most women with mild to moderate vaginal atrophy (60-90%) are asymptomatic or have symptoms that cause no distress. Clinical symptoms include the following:

• Vaginal soreness

• Postcoital burning

• Dyspareunia

• Burning leukorrhea

• Occasional spotting

Pronounced symptoms of atrophic vaginitis generally appear only after estrogen levels have been low for an extended period of time.

Early on, women may notice a slight decrease in vaginal lubrication upon arousal, which is one of the first signs of estrogen insufficiency. As the hypoestrogenic state becomes chronic, additional symptoms arise. The most common symptom is vaginal spotting, which usually results from a break in the thin vaginal mucosa. Dyspareunia may result from ulceration of the vulvovaginal epithelium.

The vagina is noted to be thin, with occasional petechia and diffuse redness and with few or no vaginal folds. A serosanguineous discharge may be present, with a pH of 5-7. A wet mount often shows white blood cells and a paucity of Lactobacillus.

Vulvar vestibulitis

Women who are first affected are usually young, sexually active, and of Caucasian origin. Most patients have endured their symptoms for several months and have empirically tried various remedies with no improvement.

Vulvar vestibulitis can be divided into primary and secondary forms, as follows:

• Primary vulvar vestibulitis (20% of cases) - Introital dyspareunia that starts from initiation of sexual activity or intolerable pain consistently present upon insertion of a tampon or vaginal speculum in women who have never been sexually active

• Secondary vulvar vestibulitis - Introital dyspareunia that develops after a period of comfortable sexual relations, tampon use, or speculum examinations

Usual symptoms include pain, soreness, burning, and a feeling of rawness that is aggravated by stress, exercise, tight clothing, coitus, and tampon use. The pain is usually not considered constant but is elicited by any attempt to enter the vagina.

Many patients complain of an irritating vaginal discharge and a vulvar burning sensation. Examination may reveal small spots of erythema around the vestibular glands, with rare ulceration. Lesions are predominantly found in the lower portion of the vestibule.[26]

Unfortunately, standard pelvic examination typically reveals no physical findings. Gentle pressure with a cotton-tipped applicator around the base of the hymenal ring and posterior fourchette usually elicits the pain.

Contact dermatitis

The diagnosis usually is based on the patient's history and physical examination. Clinical symptoms consist of varying degrees of tenderness, pain, burning, and pruritus. Urinary retention may occur in severe cases.

Pruritus is the cardinal symptom. However, an acute reaction may develop as a result of exposure to a potent irritant that involves the mucosa, leading to burning, rawness, and pain. This initially presents as red and edematous skin followed by exudation and weeping, which may lead to secondary infections. The irritant also may be potent enough to cause erosion, ulceration, or necrosis.

Repetitive exposure to weak irritants with an insufficient period of healing and restoration of skin integrity between each exposure characterizes chronic contact dermatitis. Contact dermatitis of long duration may include lichenification, scaling, thickening of the skin, and white plaques.

When the mechanism is an allergen, the symptoms may not be apparent until 24-48 hours after contact, while an irritant will elicit immediate symptoms.

Laboratory evaluation, if indicated, for a patient with vulvovaginitis includes checking vaginal pH and performing microscopy.[23] Fungal culturing may be used if the diagnosis of vulvovaginal candidiasis is uncertain.[1]

Vulvovaginal candidiasis

The diagnosis depends on the demonstration of a species of Candida --as with a wet-mount test or potassium hydroxide (KOH) preparation—and the presence of clinical symptoms. Vaginal pH usually remains normal in vulvovaginal candidiasis.[27, 28] (See the image below.)

Most studies demonstrate that 85-90% of vaginal isolates in vulvovaginal candidiasis are C albicans. As a result, fungal cultures have not been used by most clinicians as part of the initial evaluation. Moreover, there is a concern that fungal cultures are too sensitive and will detect yeast that may be colonizing the patient but not causing symptoms.

Atrophic vaginitis

History and physical examination generally provide sufficient information to diagnose atrophic vaginitis. Vaginal pH, if performed, generally is 6-7. A wet mount often shows white blood cells and a paucity of Lactobacillus. Culture and a KOH preparation usually are unrewarding.

Measurement of vaginal pH using Nitrazine paper is the single most important finding that drives the diagnostic process and should always be determined. Vaginal pH can be tested using a narrow-range pH paper. A pH above 4.5 suggests infections such as bacterial vaginosis or trichomoniasis (pH 5-6) and helps to exclude vulvovaginal candidiasis (pH 4-4.5).[3, 23, 29]

Remember, the specimen should be obtained in the mid-vagina, usually the side walls, and not the posterior fornix, since that area is contaminated by alkaline cervical mucus. Vaginal pH testing can be carried out by the patient; studies have shown good agreement between patient- and doctor-performed testing.[30, 31]

The wet-mount test involves microscopic examination of vaginal discharge or scrapings from vulvar lesions mixed with physiologic saline, using low- and high-power magnifications. Under microscopic viewing, the spores and conidia are visible. The presence of yeast blastospores or pseudohyphae can be detected in approximately 30-50% of patients with symptomatic vulvovaginal candidiasis.[17, 23]

A KOH preparation is made by placing a drop of vaginal secretion on a slide with a drop of 10-20% KOH and using a coverslip to protect the microscope lens. This technique is particularly useful in the diagnosis of candidal vaginitis, since the preparation may reveal budding filaments, mycelia, or pseudohyphae.

Adding KOH to the solution lyses white blood cells, red blood cells, and vaginal epithelial cells, making the alkali-resistant branching budding hyphae of Candida easier to see. Although this method may increase the sensitivity of the examination, however, it produces negative findings in at least one third of patients with symptomatic candidiasis. Nevertheless, positive results in combination with a normal vaginal pH, are helpful in confirming the diagnosis.

Vulvovaginal candidiasis

Some women with recurrent candidal infections opt for treatment with over-the-counter (OTC) medications, which generally are highly effective for candidiasis. Preparations for intravaginal administration of butoconazole, clotrimazole, miconazole, and tioconazole are available OTC. However, self medication with OTC preparations should be advised only for women who have been diagnosed previously with vulvovaginal candidiasis and who have a recurrence of the same symptoms.

Any woman whose symptoms persist after using an OTC preparation or who has a recurrence of symptoms within 2 months should seek medical care.[32] Unnecessary or inappropriate use of OTC preparations is common and can lead to delayed treatment for other etiologies of vulvovaginitis, possibly causing adverse clinical outcomes. Studies on women treating themselves for candidiasis revealed a 28% accuracy rate.[3]

Vulvar vestibulitis

Considerable controversy exists regarding the optimum mode of treatment for this condition. Many therapeutic regimens have been used with varying success.

Contact dermatitis

Literature is limited on treatment options. Most treatment regimens are empiric and based on clinical experience.

The cell wall of Candida is a complex glycoprotein that depends on the biosynthesis of ergosterol. Azole compounds, found in antimycotic drugs, are believed to block ergosterol production, allowing topical antimycotics to achieve cure rates in excess of 80%. Oral agents also achieve high cure rates. The oral azole agent fluconazole is approved for this indication by the US Food and Drug Administration (FDA). Therapeutic concentrations are found in vaginal secretions for at least 72 hours after the ingestion of a single 150-mg tablet.[33]  The oral triterpenoid agent, ibrexafungerp, is the first non-azole antifungal approved for vulvovaginal candidiasis (VVC) and the first drug approved in a new antifungal class for VVC in more than 20 years.[34]  

In considering treatment, distinguishing between sporadic and recurrent episodes of vulvovaginal candidiasis is of great importance. Uncomplicated sporadic vulvovaginal candidiasis usually is caused by strains of C albicans. Most of these strains exhibit sensitivity to azole-based antifungal agents and are therefore usually responsive to all forms of antifungal therapy.

To date, studies have shown no overall difference in the in vitro activity and clinical efficacy of the various azole topical agents, used in the treatment of uncomplicated cases (see Table 1, below). Thus, practitioners can begin with an empiric trial of treatment without relying on cultures. In uncomplicated cases, selection of treatment usually is based on patient preference.

A number of antimycotic regimens are available for the treatment of vulvovaginal candidiasis, including with oral and topical agents. However, drug interactions with oral usage must be taken into consideration. Hepatotoxicity secondary to ketoconazole therapy occurs in approximately 1 in every 10,000-15,000 individuals exposed to this drug. Adverse effects also can include nausea, abdominal pain, and headaches. Drug interactions may occur with simultaneous use of calcium channel antagonists, warfarin, cyclosporine, oral hypoglycemic agents, protease inhibitors, theophylline, and rifampin, to name a few.

In comparative trials of 10- to 14-day courses of therapy, the azoles resulted in higher rates of clinical and mycologic cure (80-95%) than another effective topical agent, nystatin (70-80%). In addition, the azoles have been more efficacious even when given for less than the 14 days required for nystatin.

Table 1. Suggested Treatment Options as Cited in the US Centers for Disease Control and Prevention (CDC) Guidelines for Treatment (Open Table in a new window)

Recurrent vulvovaginal candidiasis

Oteseconazole is an oral antifungal approved in April 2022 specifically to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC in women who are NOT of reproductive potential (ie, biological females who are postmenopausal or have other reasons for permanent infertility). It is contraindicated in females of reproductive potential and in pregnant females because of the risk for embryofetal toxicities. The drug exposure window is nearly 700 days based on 5 times the drug’s half-life (ie, 138 days). 

Oteseconazole is an azole metalloenzyme inhibitor that targets fungal sterol 14-alpha demethylase (CYP51). Inhibition of CYP51 results in accumulation of 14-methylated sterols, which may be toxic to fungi. 

Approval of oteseconazole was supported by positive results from phase 3 trials: two global VIOLET studies and a US-focused ultraVIOLET study, including 875 patients at 232 sites across 11 countries. Results from ultraVIOLET (N = 219) demonstrated oteseconazole was superior to fluconazole/placebo in the proportion of subjects with more than one culture-verified acute VVC episode through week 50 in the intent-to-treat (P< .001).[35]  

Several studies have shown the effectiveness of antifungal maintenance suppressive therapy for several months. Although an optimal regimen has not yet been established, treatments include ketoconazole (400 mg/day), itraconazole (50-100 mg/day), fluconazole (100 mg/wk for 6 wk), and clotrimazole (500-mg vaginal suppositories once per wk). These regimens have been used for up to 6 months.[2]

Topical boric acid[36] has been used for decades as a treatment for vulvovaginal candidiasis. Although it often is effective, it is classified as a poison and may be absorbed systematically through the vaginal mucosa. For protection, it is encapsulated in a gelatinous capsule and administered as a suppository. Treatment includes 600 mg in size 0 gelatin capsules administered intravaginally every day for 2 weeks.

In addition to medical treatment, studies have shown that ingested sucrose and lactose may support and promote the growth of yeast. Therefore, having patients limit their dietary intake of such sugars may help. Patients are also advised to wear loose-fitting, nonocclusive clothing and cotton underwear to avoid providing the warm, moist climate in which Candida tends to thrive. Some providers recommend washing clothing in hot water and using panty liners to avoid creating a reservoir for the fungus.

In November 2022, ibrexafungerp (Brexafemme) was approved by the FDA for reducing the recurrence of vulvovaginal candidiasis (RVVC). Approval was based on results from the phase 3 CANDLE study, which studied the safety and efficacy of monthly dosing of ibrexafungerp to reduce RVVC. Treated patients had a 65.4% rate of no recurrence through week 24 compared to the placebo-treated group (P=.02). The success rate continued for the ibrexafungerp-treated group over the 3-month follow-up period compared to the placebo group. (P=.034).[37]

Estrogen treatment

Accumulating evidence indicates that the symptoms of atrophic vaginitis readily respond to estrogen therapy. With treatment, mucosal thickening with glandular function can be maintained well into the postmenopausal period. Estrogen’s effect on vaginal cytology is quantified with the maturation index, using vaginal smears from the lateral walls of the upper one third of the vagina.[38, 39]

Treatment usually entails the use of topical vaginal estrogen for 1-2 weeks to alleviate symptoms. An increase in superficial cells and the vaginal maturation index occurs at levels of plasma estrogen that are barely above those of menopause. Once symptoms improve, continuation of treatment at decreased intervals is necessary for maintenance. An oral estrogen regimen can also be used.

Studies demonstrate that vaginal creams produce serum estradiol levels one-fourth those of oral estrogen but are 4-times more potent than oral estrogen on the vagina. Treatment can be continued indefinitely, although safety data for treatment beyond 1 year have not been established.

The choice of modality for local estrogen administration should be guided by patient preference, taking into account factors such as cost and convenience. A systematic review of 16 randomized trials investigating local estrogen treatment of vaginal atrophy found that creams, pessaries, and rings were all similarly effective in relieving the symptoms.[40]

Numerous studies have used different treatment regimens; treatment usually is selected based on clinician preference. The manufacturers of Premarin vaginal conjugated estrogen cream suggest 0.5-2 g applied 3-7 times per week for 3 weeks, followed by 1 week without, for 3-6 months.

Estrogen cream

The advantages of vaginal estrogen cream include lower plasma levels and greater effectiveness than with oral treatment. Disadvantages include compliance issues due to the application process itself and its messiness; as a result, the silastic vaginal ring (Estring) and vaginal tablets (Vagifem) were developed.

A randomized, multicenter, double-blind study by Kroll et al that included 550 sexually active postmenopausal women with moderate-severe dyspareunia reported that lower-dose estradiol vaginal cream (0.003%) dosed three applications/week reduced the level of dyspareunia, decreased vaginal pH, and improved vaginal cytology when compared to the placebo.[41]

Vaginal ring

The vaginal ring is placed in the vagina to release small, controlled doses of estrogen daily (7.5 mcg of estradiol).[42] Serum estrogen is slightly increased but usually remains in the menopausal range. The ring has been noted to have at least equal efficacy to vaginal estrogen cream with regard to tissue integrity and patient acceptance. It is intended to be used continuously for 90 days and can be used during sexual intercourse.[43]

Vaginal tablet

Vagifem, a vaginal tablet containing 25 g of 17-beta estradiol, has been demonstrated to be well tolerated and effective. In a 12-week, double-blind, randomized, placebo-controlled study by Eriksen et al, greater symptom improvement was seen with Vagifem than with placebo. Treatment is clinician-based, with a common regimen being 1 tablet daily followed by a twice-weekly maintenance application.[44]

Health concerns

Studies, although short-term, have not demonstrated an association between the use of unopposed estrogen and the risk of endometrial proliferation and possible subsequent endometrial carcinoma. Estradiol levels in the range of less than 70 pmol/L have been shown to be associated with atrophy of the endometrium. These forms of estrogen all maintain plasma levels well below 30 pmol/L during steady state.

In a study of 60 postmenopausal women randomly assigned to receive Estring or no treatment for 12 months, no significant increases in endometrial thickness were observed in either group. Similar results have been reported with estrogen vaginal tablets. Thus, the risk of endometrial carcinoma is considered minimal. However, any amount of estrogen absorption may be clinically relevant in a patient with breast cancer.[40]

Alternative treatments

Hormone therapy is not the only option for postmenopausal women with atrophic vaginitis. Women who cannot or do not want to take hormones may decide to use nonpharmacologic therapies, such as herbal treatments. However, although herbal treatments are used widely by women—a survey by the North American Menopause Society indicated that up to 10% of women use herbal therapies for menopausal symptoms—they remain largely unstudied by the scientific community.[45] Three agents that have been under study are dong quai, black cohosh, and isoflavones.

Dong quai

Many women in Europe and the United States have used dong quai, a traditional Chinese herb extracted from the Angelica sinensis root, for menopausal symptoms. Although US and European women use this herb alone, Chinese practitioners prescribe it in conjunction with other herbs.

In a study in which 71 women with hot flashes were given either dong quai (4.5 g daily) or placebo for 6 months, no difference in endometrial thickness or in the vaginal maturation index was found between the 2 groups. Dermatitis secondary to photosensitization is a common adverse effect of this drug.[46]

Black cohosh

Black cohosh (Cimicifuga racemosa) is marketed as a precursor of progesterone that has estrogenlike effects. It is a phytoestrogen that contains triterpene, a flavonoid, and has been used in Germany for decades to treat menopausal symptoms. Black cohosh has been found to reduce levels of luteinizing hormone, but not follicle-stimulating hormone, in menopausal women. According to a few studies, extract doses of either 2 tablets or 40 drops twice daily can safely reduce menopausal symptoms. Data are limited, however, and no information is available on toxicity. In rare cases, black cohosh can cause stomach upset. It has an additive hypotensive effect when combined with antihypertensives. The recommended dosage is for a maximum duration of 6 months.[47]

Isoflavones

Phytoestrogens are naturally occurring plant sterols that have estrogenic and antiestrogenic effects in humans. They include isoflavones (found in soybeans), coumestans (found in red clover and alfalfa sprouts), and lignans (found in oil seeds such as flaxseed).

Phytoestrogens are absorbed and converted by the intestinal flora into compounds that resemble estrogen. They then bind with and activate human estrogen receptors. If endogenous estrogen levels are high, they exhibit antiestrogenic effects; however, in postmenopausal women in whom levels are diminished, they are found to exhibit estrogenic properties.[48]

Interest in isoflavones escalated after observation that Asian women, who consume a much higher quantity of isoflavones than do Western women, experience fewer menopausal symptoms. A small study of menopausal Thai women demonstrated that only 27% of them reported menopausal vasomotor symptoms, as opposed to 85% of Western women.[49]

Studies, although limited, have demonstrated small increases in vaginal superficial cells with the ingestion of isoflavone. However, no significant increase in follicle-stimulating hormone or luteinizing hormone has been demonstrated.

Additional therapies

Other nonhormonal therapies include vaginal moisturizers and lubricants.[50] The lubricant is used just before intercourse, and the moisturizer is used long-term to relieve symptoms. Nachtigall et al compared the effect of a moisturizer (Replens) with that of conjugated estrogen cream (Premarin) in a randomized 12-week trial with 30 patients and found that, although both agents were effective, estrogen therapy was more effective in restoring vaginal elasticity and reversing vaginal atrophy. Replens was administered 3 times weekly with an applicator, and the cream was used at 1.25 mg/day.[38]

The results demonstrated that both produced lower pH levels; however, the estrogen produced a statistically significantly greater effect on vaginal elasticity within 4 weeks. The Replens increased elasticity over a longer period of time. It also reversed vaginal atrophy in 60% of patients, compared with 100% of patients receiving estrogen.

Of the treatments listed here for vulvar vestibulitis, most have not been evaluated prospectively and are based on clinical experiences reported in the literature.

Generally, no specific cure is available for this disorder, but spontaneous resolution has been reported; thus, treatment should focus on the alleviation of symptoms. Pain management has consisted of modalities such as sex therapy, behavior modification,[51] biofeedback,[51] and acupuncture.

Remedies that have been used with some success include topical application of anesthetics, such as 5% Xylocaine ointment, applied 15-30 minutes prior to intercourse. Other treatments include the use of a protective coating, such as from petroleum jelly or vitamin A and D ointment (to minimize contact with any irritating vaginal discharges); topical corticosteroids; wet compresses with aluminum acetate; and anti-inflammatory agents.

A case report by Solomons demonstrated the use of oral calcium citrate combined with a low oxalate diet. He noted that calcium oxalate crystals released in urine might act as an irritant in the development of vulvar vestibulitis. He recommended a low oxalate diet with the ingestion of calcium citrate (200 mg calcium and 950 mg citrate) to theoretically inhibit the formation of calcium oxalate crystals.[52] Many other authors have also recommend this trial of treatment; however, studies are lacking with regard to benefit.

A number of trials have used alpha interferon and have noted some success with it. The idea of using this agent against vulvar vestibulitis was initiated after alpha interferon was used successfully in the treatment of condylomata acuminata. Horowitz et al treated 17 women with severe vulvar vestibulitis with intravestibular injections of alpha interferon, administering 1 million units 3 times per week for 1 month.

The investigators noted that 15 of the 17 women demonstrated considerable improvement. Favorable response was gauged by improvement of clinical symptoms, such as dyspareunia.[53] However, recommendations at this time indicate that alpha interferon should be used as a mode of treatment for women who present with concomitant HPV infections.

Because the etiology of pain in vulvar vestibulitis is neuropathic, research has focused on pharmacologic treatment that addresses neuropathic pain. Medications such as gabapentin and pregabalin have been used with success. In a study of 152 women with vulvar pain treated with gabapentin, 98 (64%) achieved resolution of at least 80% of their symptoms.[54]

Surgery

Surgical excision may be considered as a last resort in the treatment of vulvar vestibulitis. Woodruff and Parmley developed the original surgical mode of treatment, describing a U-shaped excision of the posterior hymenal ring 0.5 cm on each side of the hymen, starting 0.5 cm below the urethra on each side. In their study, they reported that women who fulfilled the criteria of vulvar vestibulitis who underwent surgery demonstrated a success rate of 80%.[12] Most other studies have reported success rates of 60%. Postoperative complications, although uncommon, include dehiscence, hematoma, infection, uneven healing, and nodular excrescences along the suture line.

In the 1980s, excision by carbon dioxide laser microsurgery of the Bartholin gland or glands, followed by excision of the vestibular tissue, was used in an attempt to relieve pain thought to be caused by HPV. Healing was noted to be prolonged, and complications such as scarring and further pain led to the general abandonment of this technique.

The first step towards treatment of contact dermatitis is removal of the inciting agent. Patch testing may be necessary for allergen identification. Avoidance of sexual intercourse, douching, detergents, soaps, and perfumes is essential. Mild vulvovaginal reactions usually subside rapidly after the causative agent is withdrawn.

Cleansing can be accomplished by gentle flushing of the area once daily with clear water and patting the area dry. Triamcinolone ointment (0.1%) applied twice daily can help in irritant contact dermatitis. Severe lesions can be treated with wet compresses of aluminum acetate solution for 30 minutes several times per day. After each application, the vulvar skin must be kept clean and dry.

Hydrocortisone (0.5-1%) and fluorinated corticosteroids in lotions or creams may help to reduce symptoms; they are usually most beneficial in the treatment of true allergic reactions. Additional treatment can include antihistamines and sodium bicarbonate sitz baths.

Vulvovaginal candidiasis

In considering treatment for vulvovaginal candidiasis, distinguishing between sporadic or recurrent episodes of the disease is of great importance. Most strains of C albicans, the usual cause of uncomplicated sporadic vulvovaginal candidiasis, are sensitive to azole-based antifungal agents and are therefore usually responsive to all forms of antifungal therapy.

Atrophic vaginitis

Atrophic vaginitis is usually treated with topical vaginal estrogen for 1-2 weeks to alleviate symptoms. Treatment is then continued at decreased intervals for maintenance. An oral estrogen regimen can also be used.

Vulvar vestibulitis

Since no specific cure is available for vulvar vestibulitis, treatment should focus on the alleviation of symptoms.

Contact dermatitis

Hydrocortisone (0.5-1%) and fluorinated corticosteroids in lotions or creams may help to reduce symptoms of contact dermatitis. These medications are usually most effective against true allergic reactions.

Class Summary

These agents are used to treat vulvovaginal candidiasis. Topical azole antifungals achieve cure rates of 85-95%. Nystatin demonstrates a 75-80% cure rate. Oral fluconazole or ibrexafungerp have cure rate comparable to topical azole antifungals.[55]  These may be preferred by patients because of the ease of 1-time dosing.

Intravaginal and topical therapies with a variety of antifungals, such as clotrimazole, miconazole, terconazole, and tioconazole, are highly effective. Many of the preparations are now available OTC. 1-, 3-, and 7-day regimens can be used. Cure rates of 90% are reported with longer courses.

Butoconazole (Gynazole-1)

Butoconazole is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Tioconazole (Vagistat-1, Monistat-1)

This is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Clotrimazole (Desenex, Gyne-Lotrimin 3, Clotrimazole 3 Day)

Clotrimazole is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Miconazole vaginal (Vagistat 3, Miconazole 7)

Miconazole is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Terconazole (Terazol 3, Terazol 7, Zazole)

Terconazole is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Ketoconazole topical (Xolegel 2%)

Ketoconazole is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Nystatin

Nystatin is a broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing fungal cell death.

Class Summary

Oral azole and triterpenoid antifungals may be considered for single day treatment regimens. Oral antifungals are contraindicated for pregnant females.

Fluconazole (Diflucan)

Fluconazole is a synthetic oral azole antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation. 

Ibrexafungerp (Brexafemme)

Inhibits glucan synthase, an enzyme involved in the formation of 1,3-beta-D-glucan, an essential component of the fungal cell wall. It is indicated for vulvovaginal candidiasis (VVC) and reduces the incidence of recurrent VVC in adult and postmenarchal females.

Oteseconazole (Vivjoa)

Azole metalloenzyme inhibitor that targets fungal sterol 14-alpha demethylase (CYP51). Inhibition of CYP51 results in accumulation of 14-methylated sterols, which may be toxic to fungi. It is indicated to reduce incidence of recurrent vulvovaginal candidiasis (RVVC) in females with history of RVVC who are NOT of reproductive potential. 

Class Summary

These agents are used to treat extreme vaginal pruritus. Cream is for symptomatic relief, especially in pediatric vulvovaginitis.

Hydrocortisone topical (Anti-itch Maximum Strength, Itch-X)

Because of its mineralocorticoid activity and glucocorticoid effects, this is the drug of choice in treating pruritus in vulvovaginitis. The primary therapeutic effects of topical corticosteroids result from their anti-inflammatory activity, which is nonspecific (ie, they act against most causes of inflammation, including mechanical, chemical, microbiologic, and immunologic). Do not use very high-strength or high-potency agents on the face, groin, or axilla.

Class Summary

These agents are used in the treatment of atrophic vaginitis in postmenopausal women. Oral estrogen replacement also is effective and has other health benefits.

Conjugated estrogens (Premarin)

Several topical steroid preparations are available, including equine estrogen, estradiol, and dienestrol. Estrogens are indicated for atrophic vaginitis and atrophic urethritis associated with menopause.

Class Summary

These agents competitively bind to estrogen receptors, producing a nuclear complex that decreases deoxyribonucleic acid (DNA) synthesis and inhibits estrogen effects.

Tamoxifen (Soltamox)

Tamoxifen may be used for women who are very concerned about estrogen exposure. It can act as either an estrogenic antagonist or agonist, depending on the target tissue.