Vulvovaginitis Treatment & Management

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.