Vulvovaginal candidosis (yeast vaginitis, candida vulvovaginitis, or candidiasis, the term candidosis being thought of by most experts as the most accurate)³⁹ is widely regarded as a simple female problem when nothing could be further from the truth. Candida species belong to the normal flora of humans, and can exist as asymptomatic colonizers (commensals) on mucosal surfaces of the genital, urinary, respiratory, and gastrointestinal tracts as well as the oral cavity, skin, scalp and nails.⁴⁰ Candida species, without inflammation, can be identified in the lower genital tract in 10 to 20 percent of healthy women in the reproductive age group, 6 to 7 percent of menopausal women, and 3 to 6 percent of prepubertal girls.⁴¹ Candida can transform through a complex process, to a pathogen, causing isolated symptomatic vaginitis (VVC) or recurrent symptomatic vaginitis (RVVC). And, Candida can cause secondary infection in other vulvovaginal dermatologic conditions, leading to more complex vulvovaginal symptoms, e.g., when Candida albicans secondarily infects lichen sclerosus. Most vulvovaginal and Candidal infections at other body sites are superficial, but in severely immunocompromised patients, serious systemic infections can occur.⁴² Finally, the differential diagnosis for vulvovaginal itching is extensive. (See Table P-6: Differential diagnosis of irritative vulvar symptoms.)

In 2016, the genome of Candida was sequenced, giving better information on the species’ features; but details of the intricate mechanism leading from colonization to infection are still not fully elucidated, and RVVC is not fully understood. One of the greatest hopes for further information from the genome is the development of truly fungicidal anti-fungal medications. Most currently available anti-fungals are fungistatic, decreasing the fungal load, but reliant on the vaginal host inflammatory reaction to clear up the infection. However, the recent development of “fungerp” triterpenoid medications which target fungal cell walls⁴³ and novel azole medications which inhibit synthesis of fungal cell membranes and have very long half lives⁴⁴ offer the promise of fungicidal action and greater clinical efficacy in the future. In addition, vaccines targeting various components of the fungal cell wall and elements essential for attachment and tissue invasion by Candida organisms are currently in early stages of development. The large variation in and plasticity of Candida species, and the body’s immune tolerance toward commensal fungi make this work challenging.⁴⁵ Non-Candida albicans species are emerging pathogens and can also asymptomatically colonize human mucocutaneous surfaces, or produce symptomatic vaginitis or recurrent symptomatic vaginitis.⁴⁶ See non-albicans Candida below.

Epidemiology of VVC

VVC is not a reportable disease, and therefore, the information on its incidence is incomplete and based on epidemiology studies that are often hampered by inaccuracies of diagnosis and/or the use of non-representative populations.⁴⁷ Most, if not all women carry Candida in the vagina at some point of their lives, yet sometimes without symptoms of infection.⁴⁸ Identification of vulvovaginal Candida is not necessarily indicative of disease since the definition of VVC requires both signs and symptoms of vulvovaginal inflammation in the presence of Candida species. But, in 70–75% of women, a diagnosis of VVC is made at least once during their childbearing years.⁴⁹ It is estimated that 50% of initially infected women will suffer a second VVC event and 5–10% of all women will develop RVVC.⁵⁰

The incidence of VVC in symptomatic women varies depending on the location in the world, as well as the populations studied.⁵¹ The highest incidences of Candida are reported by epidemiological studies made in African countries such as Nigeria,⁵² followed by Brazil⁵³ then Australia.⁵⁴

The lowest incidences are reported in the European countries of Greece (12.1%)⁵⁵ and Italy (19.5%).⁵⁶ In India, incidence of Candida ranges from 17.7 to 20.4%.^{57 58 59} Candida glabrata has been reported as the dominant species in studies from several African and Asian countries including Nigeria, Ghana, Turkey, India, and Lebanon.⁶⁰ All of these epidemiological studies reported a higher incidence of VVC in women at reproductive age (20–40 years) than in women at menopause or in pre-pubertal girls.

Microbiology

There are more than 350 different species of Candida in nature. At least 13 Candida species cause infection in women. C. albicans is the most common.⁶¹

Other species of Candida are denoted as “non-albicans Candida,” with Candida glabrata the most common, C. tropicalis in second place, followed by C. parapsilosis and C. krusei. Culture is required to identify the species when Candida is recurrent or refractory.

Typically, a single species is identified, but two or more species have been found in 1-10% of women with VVC.^{62 63 64} Most of these mixed infections are caused by an association between C. albicans and C. glabrata.^{65 66 67}

Historically, 85–95% of Candida species identified in women with VVC were C. albicans.^{68 69} However, there are studies published during the 1990’s reporting an incidence of C. albicans below 85% and in some countries even below 50%. It has been suggested that the widespread and inappropriate use of anti-fungal treatments (self-medication and prolonged anti-fungal therapy) may lead to the selection of non-albicans species (such as C. glabrata), which are more resistant to the commonly used anti-fungal agents than is C. albicans.^{70 71}

Lactobacilli may be protective through competition with Candida for nutrients, stearic interference with Candida adherence, and elaboration of hydrogen peroxide and inhibitory bacteriocins.⁷² Production of biosurfactants by lactobacillus species can prevent fungal adhesion to epithelial walls. Lactobacillus production of organic acids such as lactate and bacteriocins exert fungistatic effects. Saturation of epithelial adhesion sites and co-aggregation (adherence of vaginal bacteria to fungal organisms) by Lactobacillus species can prevent Candida adherence to epithelial walls. Lactobacilli can also reduce the expression of genes in Candida responsible for yeast adherence and hyphal formation. And, lactobacillus species alter the host immune response to attract granulocytes and promote host immune defense.⁷³ However, at the present time, treatment with lactobacilli has not been effective in preventing antibiotic-related Candida.

Non-albicans Candida

Culture proven non-albicans Candida found in the vagina represents another challenge. Like Candida albicans, non-albicans Candida may be present, (although less commonly) as a commensal not responsible for perplexing vulvovaginal symptoms. It can also be the cause of isolated symptomatic vaginitis or recurrent symptomatic vaginitis, or act as a source of secondary infection in women with an epithelial disorder or with contact irritant use. Non-albicans yeast, most commonly C. glabrata, may be responsible for up to 33% of recurrent cases of candidosis.⁷⁴ In fact, non-albicans species have been more commonly isolated among patients with RVVC than in women with sporadic VVC,⁷⁵ possibly, as mentioned above, due to a higher anti-fungal exposure and widespread use of over the counter anti-mycotics among patients with RVVC.⁷⁶

Pathogenesis of Candida

Access of Candida to the vagina

Candida gains entry to the vagina by crossing from the rectum over the perineum,⁸⁷ but it has long been known that decreasing gastrointestinal carriage of Candida by oral administration of nystatin does not prevent recurrent symptomatic vaginal infection.⁸⁸ A systematic review from an interdisciplinary and environmental medical point of view has been undertaken and failed to draw conclusions about the patho-genetic significance of intestinal Candida colonization.⁸⁹

Candida infection may arise (less commonly) after sexual contact,⁹⁰ or from relapse or persistence of the organism after previous Candida infection.

Colonization

In the vagina, Candida may live in harmony as a colonizer next to vaginal bacteria. The natural history of asymptomatic vaginal yeast carriage is unknown, but may exist for months or years.⁹¹

Vertical transmission from mother to infant during childbirth allows for early establishment of colonization of the oral cavity and the rectum with Candida, where its interaction with other resident microbiota and host immunity prevent transition from commensal organisms to pathogens. Extragenital colonization has been implicated as a reservoir of genital recolonization in patients with recurrent vulvovaginal candidiasis.⁹² At the vaginal level, epithelial cells under the influence of reproductive hormones⁹³ provide a mechanical barrier, recognize and process antigens, secrete immune mediators and orchestrate the vaginal immune system in a delicate balance of protection against pathogens while allowing the immune tolerance necessary to accept semen and a developing fetus.⁹⁴

Symptomatic candidal vaginitis (VVC)

Besides colonization, Candida has the ability to cause symptomatic vaginitis by transformation to an invasive pathogen. Candida may exist as a spore or a filament (hyphae or pseudohyphae). All forms are thought to play a role in the progression of vaginal infection in women.⁹⁵ Transformation from colonization to infection involves a complex interaction of:

(1) host inflammatory responses (discussed below)

(2) Candida virulence factors.⁹⁶ While it is usually assumed that the transition from asymptomatic colonization to symptomatic candidiasis occurs following a perturbation or loss of local defense mechanisms, this transition may also occur because of factors that enhance fungus virulence.⁹⁷ These include:

1. Morphologic plasticity: albicans is a polymorphic fungus that can reversibly transition between yeast, pseudohyphal and hyphal forms. The unicellular yeast form is commonly regarded as a harmless colonizer, but transition to the hyphal form allows the organism to adhere to and invade epithelial cells, resulting in extensive host cell damage. Host membranes are weakened by degradative enzymes secreted at the hyphal tip and pressure exerted by the elongating filament is then sufficient to penetrate the host cell.
2. Phenotypic plasticity: albicans has the capacity to switch from a white phenotype producing smooth white colonies to gray and opaque phases which are less virulent. This switching between white and opaque phenotypes helps C. albicans evade host immune responses, as opaque cells are less susceptible to phagocytosis by macrophages and are able to evade killing by neutrophils.
3. Genomic plasticity: albicans is capable of gross chromosomal rearrangement, aneuploidy, and loss of heterozygosity when exposed to different stresses. This allows the organism to adapt to a changing environment by changing the number of specific genes on a given chromosome. For example, amplification of two resistance genes on the left arm of chromosome 5 (ERG11 and TAC1) is associated with azole resistance.⁹⁸
4. Fungal products: albicans possesses multiple redundant pathogenic mechanisms for triggering inflammatory processes within the host. Candida virulence factors are genetically controlled, including an estradiol binding protein (EBP),⁹⁹ multiple mechanisms for adherence of Candida to the epithelial cell prior to invasion, as well as ability for hyphal and biofilm formation.¹⁰⁰ In addition, extracellular proteinases of C. albicans trigger immune responses locally and systemically.¹⁰¹ C.albicans has the ability to modulate phagocytosis by host neutrophils and macrophages, and endocytosis of C. albicans into epithelial cells both contributes to its invasiveness and stimulates phagocytic cells to produce inflammatory cytokines. In the non-albicans candida species, C. glabrata has highly efficient adhesion to various surfaces due to a range of adhesins, high stress resistance, and the shortest replication time of all Candida species. C. glabrata strains have an intrinsic resistance to azole antifungal medications, and mixed biofilms consisting of C. glabrata and C. albicans lead to more robust and complex structures and improve antifungal resistance.¹⁰².
5. Drug resistance mechanisms: One of the main routes of resistance is the over-expression of efflux pump-related genes that results in decreased drug concentration within fungal cells (MDR1 genes in fluconazole resistance, and CDR1/CDR2 genes in resistance to all azoles). Overexpression of the ERG genes involved in ergosterol biosynthesis and biofilm formation also results in drug resistance among Candidal species.¹⁰³

Since many Candida infections occur without a clear risk factor,¹⁰⁴ it appears that focus on host inflammatory risk factors and Candida virulence factors is important.

At this time, new therapies are not available to address immune factors, but it is helpful to discuss with affected women that immune factors related to both the Candida organism and the vagina may cause their complex problems.

Recurrent vulvovaginal Candida (RVVC)

The host’s immune response is a crucial element of pathogenesis and host pathogen interaction.¹²² The immune system is separated into two branches: humoral immunity, for which the protective function of immunization arises from antibodies, complement proteins, and certain antimicrobial peptides located in the cell-free bodily fluid or serum (humor), and cellular immunity, for which the protective function of immunization is associated with cells: phagocytes, antigen-specific cytotoxic T-lymphocytes, and sometimes, the release of various cytokines in response to an antigen. It is established that cell wall constituents of Candida species have antigenic properties that can evoke both humoral and cellular host immune responses during the course of infection.

Cell mediated immune response

The cell-mediated immune response is clearly important in the host defense against Candida, as reflected by the higher prevalence of infections among individuals whose cellular immune systems are impaired. As discussed above, an early hypothesis was that the systemic cell-mediated immunity of the host was defective, but current consensus today is that women with RVVC have a local vaginal immune deficiency.¹²⁴ This local immune deficiency has yet to be clearly defined.

The exact mechanisms of induction of cell-mediated immunity in VVC and RVVC have not yet been elucidated. T cells can be identified in large numbers in the human vagina. Their characteristics suggest migration to the vaginal epithelium in response to local antigenic stimuli and/or inflammatory chemokines.^{125 126}

Neutrophils may also be implicated in host defense against Candida infection. Studies have shown that granulocyte colony-stimulating factor (G-CSF) increased neutrophil-mediated damage to pseudohyphae of C. albicans, perhaps in association with IFN-gamma.^{127 128} Yeast hyphal formation and expression of ECE1 which encodes for the hypha-expressed toxin candidalysin are the crucial virulence determinants driving neutrophil recruitment.¹²⁹

Humoral immune response

The role of the humoral immune response in preventing disease progression during Candida infection has been unclear and controversial.^{130 131} Some of the host immune response to candidal infection may be modulated by elements of the vaginal microbiome. L. crispatus, one of the dominant members of the vaginal microbiome, can diminish C. albicans virulence and enhance local immune response of vaginal epithelial cells by modulating the immune cytokines and chemokines profile, i.e. upregulating IL-2, IL-6, IL-17, and downregulating IL-8. Lactobacilli can also inhibit biofilm formation by C. albicans. Also, low pH and bactericidal compounds secreted by Lactobacilli tend to suppress Candida overgrowth and its transition from a virulent yeast form to virulent hyphal form. Surfactant protein A, produced in the vaginal mucosa, provides host defense by opsonizing pathogens, altering levels of pro-inflammatory cytokines, stimulating oxidative burst by phagocytic cells and promoting differentiation of antigen presenting cells, thereby linking innate with adaptive immunity.¹³²

However, work with polyclonal and monoclonal antibodies, as well as mannan-specific IgG antibodies which trigger both the classical and alternative complement pathways, ¹³³ suggests that development of a vaccine or short-term protective antibodies may be feasible. Indeed, in both immunocompetent and immunocompromised mice, a vaccine against C. albicans conferred reduced fungal burden and improved survival.¹³⁴

Host risk factors for Candida

Pregnancy and estrogen

Diabetes mellitus

Uncontrolled diabetes predisposes to yeast vaginitis, but candidiasis is not increased when the disease is well controlled.¹³⁹ In glucose tolerance tests on women with recurrent candidiasis, there was no increased frequency of abnormal test results compatible with diabetes or pre-diabetes. Plasma glucose values were within the normal range, but were substantially higher than controls, suggesting that a diet high in refined sugars could contribute to the risk of candidiasis.¹⁴⁰ Clear support for elimination of all carbohydrates does not exist in medical evidence. Women with type 2 diabetes appear prone to colonization and infection by non-albicans Candida species. Elevated plasma glucose levels and subsequent glucosuria induce proteins in Candida which favor yeast adherence. Treatment with sodium-glucose cotransporter 2 inhibitors may increase the risk for vulvovaginal candidiasis.¹⁴¹

Antibiotics

Estimates of the frequency of candidosis following antibiotic use ranges from 28% to 33%,¹⁴² thus, most women who receive antibiotics do not develop candidiasis. All antimicrobials are thought to cause candidosis by eliminating the protective bacterial flora, allowing overgrowth of Candida in the gastrointestinal tract, vagina, or both.¹⁴³ Low numbers of lactobacilli have been found in vaginal cultures from some women with Candida vaginitis.¹⁴⁴ But administration of lactobacillus (oral or vaginal) during and for four days after antibiotic therapy does not prevent post-antibiotic vulvovaginitis.¹⁴⁵

Gastrointestinal tract

Although oral nystatin does not prevent vaginal Candida infections,¹⁴⁶ there may be a link between symptomatic vaginal Candida infections and the gastrointestinal tract. In a study of both HIV infected and non-infected women, bowel movements appeared to correlate with fungal growth, as diarrhea was associated with an increase in vaginal fungal growth. Women who had diarrhea in the past 30 days were approximately twice as likely to have fungal growth than those who did not have diarrhea, which reached statistical significance in both groups.¹⁴⁷

Immunosuppressive medications and disease

Use of corticosteroids is likely to be associated with recurrent Candida because of local suppression of immunity.¹⁴⁸ Candida infections are also more common with use of immunosuppressive drugs, and with HIV infection.¹⁴⁹

The long term administration of fluconazole in HIV positive individuals for prophylaxis against other fungal opportunistic infections has resulted in an increased prevalence of non-albicans Candida species in this population.¹⁵⁰

Behavioral factors

Contraceptives

Contradictory results reported from different studies make the relationship between the OCP and Candida a controversial topic. Increased yeast colonization is reported in users of intrauterine contraceptive devices, sponges and diaphragms, and condoms, with and without spermicides.¹⁵¹ An extensive study of college students did not show an increase in the risk of symptomatic vulvovaginal candidosis in users of oral contraceptives, diaphragms, condoms, or spermicides.¹⁵²

At least two studies have suggested that recurrent Candida vulvovaginitis in IUD user may be related to the ability of some species to attach to the IUD and form a biofilm rather than related to the IUD itself. Spermicides are not associated with Candida infection.¹⁵³.

Sexual activity

Women who are not sexually active often develop vulvovaginal candidiasis; the incidence of the disease increases dramatically in the second decade of life, with the onset of sexual activity.¹⁵⁴ Candida occurrence declines in women older than 40 years, but can resurface with use of estrogen after menopause.

The theory that recurrences are caused by re-infection of the woman by her male sexual partner has been suggested repeatedly, with some data suggesting that sexual transmission does occur.¹⁵⁵ Candida species may be harbored in the male gastrointestinal tract, semen, urine, and oral cavity.¹⁵⁶ Male colonization is associated with vaginal colonization, often with the same strain.¹⁵⁷Reed et al¹⁵⁸ studied sexual behaviors that were associated with recurrences of C. Albicans vulvovaginitis. Vaginitis was found to be unrelated to the presence of Candida in various body sites of the female or her male partner prior to the recurrence. Even Candida carriage in the vagina failed to predict subsequent symptomatic Candida vulvovaginitis. The following sexual risk factors for recurrent Candida vulvovaginitis were, however, identified: the female masturbating with saliva or cunnilingus from her partner, and the male masturbating with saliva or having had a younger age at first intercourse (reason unclear). They also found evidence that frequency/periodicity of sexual intercourse is associated with acute Candidal vaginitis frequency. Receptive oro-genital sexual intercourse consistently emerges as a risk factor for Candida.¹⁵⁹ It is not clear whether this is related to transmission of the organism. Treatment of partners is not recommended unless they have symptoms.¹⁶⁰ Occasionally, male partners of asymptomatic female carriers of Candida develop transient post-coital penile erythema and pruritus, suggesting inflammation from a hypersensitivity reaction. Women who exclusively have sex with women do not appear to have an increased risk of vulvovaginal infection.¹⁶¹

Other factors

Chemical contact, atopy, local allergy, or hypersensitivity reactions could alter the vaginal milieu and facilitate transformation from asymptomatic colonization to symptomatic vaginitis.¹⁶² Evidence is weak and conflicting regarding risk from sanitary pads and tight-fitting clothing.¹⁶³

Both vaginal colonization and transition to infection have been linked to certain host genetic factors, including mannose-binding lectin polymorphisms, ABO-Lewis non-secretory blood group phenotype, and Y238X polymorphism in the Dectin-1 gene.¹⁶⁴

Clinical manifestations

The clinical spectrum of symptomatic vaginitis varies from an acute, exuberant, exudative form with copious, white, vaginal discharge with little to no odor, and large numbers of germinated yeast cells, to the absence of discharge, fewer organisms, but the same severe pruritus. Clinical signs and symptoms in infections caused by different Candida species are a source of debate; C. glabrata and C. parapsilosis tend to be associated with milder, often absent symptoms.¹⁶⁵ Vulvar pruritus is the dominant feature of candidal vulvovaginitis. Women may also complain of dysuria (typically perceived to be external or vulvar rather than urethral), soreness, irritation, and dyspareunia. There is often little or no discharge; but the typical white and clumpy (curd-like) secretions may be seen. Symptoms are often worse in the week prior to menses.

 

However, the secretions may also be thin and loose, indistinguishable from the discharge of other types of vaginitis.

Diagnosis of Candida by simple inspection of vaginal secretions is not possible. Some patients, primarily those with C. glabrata infection, have little discharge and often only erythema on vaginal examination.¹⁶⁶ Evidence of excoriation may be present. Candida albicans is also a frequent cause of vulvar fissuring.

Diagnosis of Candida

Reliable diagnosis of Candida cannot be made on history and physical examination alone. Diagnosis requires:

1. visualization of blastospores or pseudohyphae on saline or 10% KOH microscopy or
2. a positive culture in a symptomatic woman. A culture is of no value if the woman has recently used anti-fungal treatment. Repeating the culture if a woman continues to be symptomatic after treatment is important. Some experts do not recommend yeast cultures if microscopy is negative. On the other hand, microscopy skills vary widely, artifacts (hair and fibers, overlapping cells) abound, and the cost of culture has come down. A negative culture in the presence of vulvovaginal symptoms educates the woman that Candida albicans is not the reason for her discomfort, and encourages the clinician to look for other explanations.

In addition to vaginal yeast culture, there are a number of newer diagnostic technologies on the market. They vary in sensitivity, specificity, which species of Candida are tested for and reported, and availability in different health care settings. These point-of-care tests are considerably more expensive than in-office microscopy, but may be helpful in the setting of recurrent symptoms or low fungal loads.¹⁶⁷

• DNA Probes:

1. 1. 1. Affirm VP III (BD): Probe for Candida, Gardnerella, and Trichomonas. 58% sensitive, 100% specific. Detects “Candida species” without reporting individual speciation.

• Polymerase Chain Reaction (PCR) Assays:

1. 1. 1. BD Max Vaginitis Panel (BD): 90.7% sensitive, 93.6% specific. Detects Candida Group (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis), C. glabrata, and C. krusei. FDA cleared.
      2. SureSwab Candidiasis (Quest Diagnostics)

• Nucleic Acid Amplification Tests (NAATs):

1. 1. NuSwab (LabCorp): 97.7% sensitive, 93.2% specific. Detects C. albicans and C. glabrata.
   2. SureSwab Advanced Candida Vaginitis (CV), TMA (Quest Diagnostics): Employs transcription mediated amplification (TMA). Reports C. albicans, C. parapsilosis, C. tropicalis, C. dubliniensis, and C. glabrata.

In addition, there is an emerging market for at-home testing for vaginitis. These tests range from simple pH testing for bacterial vaginosis, to immunoassays and NAATs which test for Candida and other vaginal and cervical pathogens. Some platforms report results at the point of testing, and some need to be sent out and will report results within 2 to 5 days. There is currently little to nothing in the medical literature evaluating the sensitivity, specificity, and accuracy of these tests, and their cost can be substantial, but some of them offer the convenience and privacy of home self-collection.

Pap smear is positive in 25 percent of patients with culture positive, symptomatic vulvovaginal candidiasis. ¹⁶⁸ But since the cells evaluated on a Pap smear are from the cervix, and are not affected by Candida vaginitis, the Pap smear is not a sensitive test.¹⁶⁹ If Candida is found on a Pap smear of an asymptomatic woman, treatment is not required.

Most women with RVVC are HIV negative. Only women with RVVC who have risk factors for HIV infection should be tested.¹⁷⁰

It is well established that self-diagnosis is frequently inaccurate.¹⁷¹ In a study that administered a questionnaire to 600 women to assess their knowledge of the symptoms and signs of vulvovaginal candidiasis (and other infections) after reading classic case scenarios, only 11 percent of women without a previous diagnosis of vulvovaginal candidiasis correctly diagnosed this infection. Women who had had a prior episode were more often correct (35%) but were likely to use over-the-counter drugs inappropriately to treat other, potentially more serious, gynecologic disorders. In another report, the actual diagnoses in 95 women who self-diagnosed vulvovaginal candidiasis were: vulvovaginal candidiasis (34%), bacterial vaginosis (19%), mixed vaginitis (21%), normal flora (14%) Trichomonas vaginitis (2%), and other (11%). Women with a previous episode of vulvovaginitis candidiasis and those who read the package insert for their over-the-counter medication were not more accurate in making a diagnosis than other women.¹⁷².

Diagnosis may be confounded when co-existent causes of symptoms (itching e.g.) are present, such as non-albicans Candida and a skin disorder, or Candida and vulvodynia. Consideration of the multiple other sources of vulvovaginal irritation prior to treatment of the culture positive Candida is important. (Consult Table P-6). Confirm whether the vulvovaginal epithelium appears quiet or inflamed. Lack of erythema or lesions suggests that inflammation from yeast is not present. Conversely, presence of erythema and/or alterations in skin texture or integrity may be signs of either Candida or a vulvar skin condition, irritant use, or other conditions, as listed in the table. Loss of vaginal architecture requires consideration of lichen sclerosus and/or biopsy.

Many vulvovaginal experts do not treat a positive culture for non-albicans Candida unless they are convinced that symptoms arise from the Candida and not another source. Watching and waiting, after explanation to the patient that the non-albicans yeast may be an innocent bystander, may show that symptoms are not significant and culture stays positive in a patient whose irritative symptoms do not add up to a diagnosis of Candida vulvovaginitis. It is possible that the patient has vulvodynia with irritative symptoms suggesting yeast if they have been present repeatedly over time when cultures have been negative. If the conditions in Table P-6 are eliminated, vulvodynia is the diagnosis.

Over a twenty five years ago, Candida albicans was classified as uncomplicated or complicated.¹⁷³ The classification has been accepted internationally.¹⁷⁴

Table P-5: Uncomplicated and complicated Candidiasis (Candidosis/Candida vulvovaginitis)¹⁷⁵

As discussed under Diagnosis, many women presenting with irritative vulvovaginal complaints are initially treated for Candida. Table P-6 shows the lengthy differential for pruritic and irritative vulvovaginal complaints. It is also important to recognize that Candida can occur concomitant with, or as a secondary infection with many of these conditions.

Table P-6: Differential diagnosis of irritative vulvar symptoms

Treatment of uncomplicated candida vulvovaginitis

Treatment of uncomplicated candida vulvovaginitis can be any oral or vaginal azole. There are no significant differences in efficacy among topical and systemic azoles (cure rates >80 percent for uncomplicated vulvovaginal candidiasis).¹⁷⁶ There are, however differences in the base ingredients. Miconazole, terconazole and butoconazole all contain propylene glycol to which many women are sensitive. They will tell you they had an “allergic” reaction to one of these topical drugs, meaning they had immediate contact irritation with redness and burning. Clotrimazole has no propylene glycol and is less likely to cause irritation. It is our preferred topical azole choice.

A single dose of fluconazole 150 mg orally is effective and usually preferred by women to the topical treatments, although it may take up to 48 hours before symptoms abate. Fluconazole interacts with some other drugs so careful review of medications being taken should be reviewed.^{177 178} In addition, in a nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Please see the Pregnancy section under Treatment for further information regarding use of fluconazole in pregnancy.

In women susceptible to symptomatic yeast infections with antibiotic therapy, a dose of fluconazole (150 mg orally) at the start and end of antibiotic therapy may prevent post-antibiotic vulvovaginitis.

Uncomplicated infections usually respond to treatment within a couple of days. There is no medical contraindication to sexual intercourse during treatment, but it may be uncomfortable until inflammation improves. Treatment of sexual partners is not indicated.¹⁸⁰.

Table P-7: Treatment for uncomplicated Candidiasis (Candidosis/Candida vulvovaginitis) (*= most frequently used regimen)

Treatment of complicated candida vulvovaginitis

Women with severe inflammation or factors associated with complicated Candida vulvovaginitis are unlikely to respond to short courses of topical anti-fungal drugs or a single dose of fluconazole. Observational series have reported that these patients require 7 to 14 days of topical azole therapy, rather than a one to three day course.¹⁸¹ A randomized trial demonstrated that two doses of oral therapy 72 hours apart were more effective than one dose.¹⁸² Comparative trials of topical versus oral treatment of complicated infection have not been performed. Since the oral anti-fungals can take 48 hours or more to reduce inflammation and promote improvement of symptoms, a topical anti-fungal or a low potency topical corticosteroid applied to the vulva (in addition to the oral medication) for 48 hours can be helpful.

Table P-8: Treatment of complicated candida vulvovaginitis (intractable Candida Albicans, non-pregnant patient)

Treatment of recurrent Candida vulvovaginitis (RVVC)

Recurrent vulvovaginal candidiasis is defined as three or more episodes of symptomatic infection within one year. Vaginal cultures should always be obtained to confirm the diagnosis and to identify less common Candida species. In most people, recurrent disease is due to relapse from a persistent vaginal reservoir of organisms or endogenous reinfection with an identical strain of susceptible C. albicans, but 10-20% of recurrent infections are from a different candida strain, often a non-albicans species. Some patients exhibit an immune hyper-reactivity to Candida due to mutations and genetic polymorphisms of innate immune genes which alter the vaginal mucosal immune response to Candida challenge.

Treatment strategy for recurrent infections includes an induction phase followed by maintenance:

Induction: Any topical agent vaginally X 7-14 nights, or oral fluconazole 150 mg orally every 72 hours for three doses, or Itraconazole 200 mg orally twice daily X 3 days

Topical induction regimens include:

• Clotrimazole 1% vaginal cream for 7-14 nights
• Miconazole 2% vaginal cream for 7-14 nights
• Miconazole 100 mg vaginal suppository for 7-14 nights
• Clotrimazole 2% vaginal cream for 3-7 nights
• Miconazole 4% vaginal cream for 3-7 nights
• Miconazole 1200 mg vaginal suppository once
• Miconazole 200 mg vaginal suppositories for 3-7 nights
• Tioconazole 6.5% ointment for one night
• Terconazole 0.4% vaginal cream for 7-14 nights
• Terconazole 0.8% vaginal cream for 3-7 nights
• Terconazole 89 mg vaginal suppository for 3-7 nights
• Butoconazole 2% vaginal cream single dose

Maintenance: Fluconazole 150 mg orally once per week X 6 months, or Itraconazole 100-200 mg orally twice weekly for 6 months, or miconazole 2% vaginal cream 5 gms vaginally twice weekly X 6 months, or miconazole 1200 mg vaginal suppository once weekly X 6 months, or clotrimazole 1% vaginal cream 1 applicator twice weekly X 6 months, or terconazole 0.4% vaginal cream twice weekly X 6 months.

After 6 months of suppressive therapy, a trial of drug discontinuation is recommended. Some patients will enjoy a prolonged remission after maintenance, but up to 55% will relapse and will need longer term suppression, often for additional months or years. Due to the safety profile and low plasma concentrations of once-weekly 150 mg fluconazole, most experts do not recommend laboratory monitoring during maintenance therapy.¹⁸³

Oteseconazole was FDA approved in 2022 as a new oral azole antifungal to reduce the incidence of recurrent candida vulvovaginitis (RVVC). This is the first drug to be approved in the US specifically for treatment of RVVC. Oteseconazole is active in vitro against most isolates of C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. lusitaniae and C. dubliniensis. It is active against fluconazole-resistant isolates. Its mechanism of action is the same as other azoles, inhibition of fungal sterol 14⍺-demethylase (CYP51), an enzyme which aids in synthesis of fungal cell membranes. Adverse effects include headache and nausea. The drug has a 128 day half-life, and persists in tissues for many months. In two clinical trials oteseconazole recipients had fewer RVVC episodes and experienced a greater recurrence-free time interval compared to patients receiving placebo during a 48 week study period. Ocular abnormalities were observed in the offspring of pregnant rats given oteseconazole, and the drug is contraindicated in females of reproductive potential (including those using effective contraception) and in pregnant and lactating women.The drug should be taken with food to aid absorption and swallowed whole (not chewed, crushed, dissolved or opened. It is not recommended in patients with renal impairment or severe hepatic impairment. The medication comes in a blister pack to facilitate dosing. The cost of an 18 capsule course of therapy in 2022 was $2700.¹⁸⁴.

Single Drug RVVC Treatment with Oteconazole: 600 mg orally on day 1, 450 mg orally on day 2, followed by 150 mg orally once weekly for 11 weeks, starting on day 14.

Dual Drug RVVC Treatment: Induction with fluconazole 150 mg orally on days 1, 4, and 7. Then suppressive therapy with oteseconazole 150 mg orally once a day for 7 days on days 14 through 20, followed by oteseconazole 150 mg orally once per week. ¹⁸⁵

A 90 percent cure has been achieved with intravaginal flucytosine cream 10% (5 g vaginally nightly for two weeks),¹⁹⁰ but the expense of the medication is prohibitive for some. Amphotericin B suppositories (50 mg intravaginally nightly for 14 days) are also of value in the treatment of non-albicans yeast. Boric acid capsules, amphotericin, and flucytosine cream are not available commercially and must be made by a compounding pharmacy.

Table P-9: Treatment of non-albicans yeast (not always necessary: rule out other causes to be sure non-albicans candida may be causing symptoms)

Pregnancy

Treatment of Candida in pregnant women often fails to clear the pathogen and is usually indicated only for relief of symptoms. There is no association with adverse outcomes from vaginal candidiasis in pregnancy.¹⁹¹ Any of the topical azoles used vaginally for seven days is appropriate. Vaginal nystatin is another option, for 7 to 14 days. Avoid fluconazole, flucytosine, boric acid, amphotericin B and itraconazole in pregnancy.

There are several published case reports of birth defects in infants whose mothers were treated with high-dose fluconazole (400-800 mg/day) for serious and life-threatening fungal infections during most or all of the first trimester.^{192 193} The features seen in these infants include cranio-facial abnormalities, bony abnormalities, muscle weakness and joint deformities, and congenital heart disease. Based on this information, the pregnancy category for fluconazole indications (other than vaginal candidiasis) has been changed from category C to category D. ¹⁹⁴ The pregnancy category for a single dose of fluconazole 150 mg to treat vaginal candidiasis has not changed and remains category C. Pregnancy category D means there is positive evidence of human fetal risk based on human data but the potential benefits from use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks.

A US based population cohort study found that compared with topical azoles, oral fluconazole use in early pregnancy was associated with an increased risk of musculoskeletal malformations but not conotruncal malformations or oral clefts. This resulted in 12 additional incidents per 10,000 pregnancies, for a relative risk of 1.30.¹⁹⁵. And in a 2020 meta-analysis of 9 current studies between 2000 and 2014, first trimester exposure to fluconazole was associated with an increased prevalence of heart defects in offspring in both low dose (OR 1.95) and any dose (OR 1.79) cohorts. No association was found between gestational exposure and increased risk of spontaneous abortion or stillbirth. The author’s conclusion was that fluconazole should be regarded as a human teratogen and should be prescribed with caution in pregnant women and women of childbearing potential.¹⁹⁶

Alternative treatments

There is no evidence from randomized trials that garlic, tea tree oil, yogurt, or other products containing live lactobacillus species, or douching is effective treatment for or prevention of vulvovaginitis due to Candida albicans.

Gentian violet

Formerly a frequent treatment for Candida, it has fallen into disuse as treatment technology for yeast evolved. It is reported to affect chitin production on the yeast’s cell wall, and is suggested for combination with topical antifungal cream at night with repeat in seven days.¹⁹⁷ Vulvovaginal irritation and staining of clothing are problems associated with painting the vagina with gentian violet.Safety of gentian violet has come into question. One study in mice demonstrated dose-related carcinogenic potential at several different organ sites. ¹⁹⁸ Gentian violet has also been linked to cancer in the digestive tract of other animals. ¹⁹⁹ It is generally considered safe for use on children and breastfeeding mothers. It has even been applied to the mouth and lips of premature infants, and has a long history of safe use. La Leche League recommends gentian violet for thrush on the nipple.²⁰⁰ However, in large quantities, gentian violet may lead to ulceration of a baby’s mouth and throat and is linked with mouth cancer. ²⁰¹

Epidemiology

In 2019, a systematic review and meta-analysis of global BV cases among reproductive-aged women found a 23-29% prevalence across all regions.²⁰⁴

Racial, ethnic, and geographical variations exist but the reasons are unclear. A 2013 global epidemiological study showed differences in populations worldwide with higher rates of BV in women from South and East Africa (68% in Mozambique, 51% in Lesotho, 44% in Kenya, 37% in Gambia) than in women from West Africa (7% in Burkina Faso). Rates in Norway were 24%, Turkey 23%, and Poland 19%. In Southeast Asia, Australia, New Zealand, and Indonesia, rates are usually greater than 30%. Prevalence is lower in Latin American and the Caribbean except in Jamaica. The prevalence in Australia was determined to be 4.7% in 2008.²⁰⁵ In a 2019 study which mostly corroborated these numbers, North American black and Hispanic women had significantly higher (33% and 31% respectively) prevalence of BV compared with other racial groups (white 23%, Asian 11% (p<0.01)).²⁰⁶ “This disparity persisted when study populations were classified as majority (>50%) black women or majority non-black women, with approximately 2-fold higher prevalence among majority black study populations (46.5%; 95% CI, 37.5–55.6 vs. 21.3%; 95% CI, 16.7–26.3; P < 0.001).”²⁰⁷

In this same study, among pregnant women, BV prevalence ranged from 11.7% in South Asia (95% CI, 9.0–14.7) to 33.2% in Latin America and the Caribbean (95% CI, 14.8–54.7). Within the United States, the prevalence of BV in pregnancy was highest among black (49.0%; 95% CI, 40.2–57.8) and Hispanic women (42.7%; 95% CI, 36.4–49.1) and lowest among Asian (20.3%; 95% CI, 5.4–41.2) and white women (19.9%; 95% CI, 8.0–35.5)²⁰⁸

Etiology

The cause of BV is still unknown, but the clinical manifestations of the disorder are well documented. As we learn more about the normal vaginal microbiome of reproductive age women, we also learn about the changes in microbiota that culminate in these distressing symptoms. Researchers are looking into the vaginal microbiome for both a cause and a cure. Despite subtle variations between ethnically and geographically diverse groups of people, the normal vaginal microbiome is predominantly populated by hydrogen peroxide and lactic acid-producing “good bacteria,” Lactobacillus species.²⁰⁹ These bacteria create the low pH environment (usually 4.0 to 4.5, with some groups normal at 5.0) present in healthy vaginas. When Lactobacilli predominate, there are fewer species in the normal microbiome. By contrast, BV is described as a disturbed microbiota dominated by increased numbers of gram-positive cocci and gram-negative bacilli: mixed anaerobes which cause the pH to be elevated.²¹⁰ Concentrations of bacteria increase 100 to 1,000-fold in women with BV.²¹¹

The type of dominant bacteria in BV can vary. A 2011 study found the phylotypes most likely to correlate with a high Nugent score (the test used to identify BV in research settings) were Aerococcus, Anaeroglobus, Anaerotruncus, Atopobium, Coriobacteriaceae.’Dialister, Eggerthella, Gardnerella, Gemella, Megasphaera, Mobiluncus, Parvimonas, Peptoiphilus, Prevotella, Porphyomonas, Prevotellaceae_1, Prevotellaceae_2, Ruminococcaceae, and Snethia .²¹² In 2005, researchers found that women with BV had a mean of 12.6 bacterial phylotypes compared with 3.3 in controls. Three new bacteria in the Clostridiales order were found and named “bacterial vaginosis-associated bacteria” (BVAB).²¹³ Prevotella, previously thought to be rare in vaginal isolates, was found in 68.5% of cases of BV, with abundance ranging from a few percent to 45%. Prevotella spp. have been shown to positively affect the growth of Gardnerella vaginalis and Peptostreptococcus anaerobius by producing key nutrients for these species, such as ammonia and amino acids. Since both of these species have been linked to bacterial vaginosis, the wide distribution of Prevotella spp. in the vaginal microbiota might be a factor that facilitates BV.²¹⁴

As the Lactobacillus population decreases, pH rises, overgrowth of anaerobes occurs, and large amounts of proteolytic carboxyase enzymes are produced. These are capable of breaking down vaginal peptides into volatile and malodorous amines that are associated with increased transudation from the vaginal epithelium and exfoliation of squamous epithelial cells. While not known to be the causative agent for BV, Gardnerella vaginalis appears to be instrumental in providing a matrix (or scaffolding) for development of a treatment-resistant vaginal biofilm.²¹⁵

Current thinking places the G. vaginalis biofilm at the heart of the initiation and progression of BV.²¹⁶ Epithelial cells dotted with bacteria exfoliate from the biofilm, creating the “clue cells” that are diagnostic of BV.²¹⁷ (It is important to remember that, while Gardnerella was detected in culture samples from nearly all symptomatic women with bacteral vaginosis, it is also found in approximately 50% of the vaginal microflora of healthy women. It is possible that there are species of Garnerella that are pathogenic and others that are not.)²¹⁸²¹⁹ Biofilms may be related to persistence or recurrence of bacterial vaginosis, as organisms in the biofilm state are less susceptible to antibiotic therapy.

Extracellular DNA (eDNA) has been found to also play a role in building the stable matrix of the BV biofilm. DNase has been used, in more than one in vitro study (and partially in an in vivo study), to both prevent new biofilm formation and also to liberate G. vaginalis from existing biofilms, reducing the density of the biofilm and possibly making it more reponsive to antimicrobials.²²⁰

Although there is no clinical evidence of inflammation with BV (no WBCs on wet mount), some research points to BV as a pro-inflammatory condition with specific BV-associated bacteria eliciting the production of pro-inflammatory cytokines.²²¹

The prevalence of dysbiosis of the VMB and BV in racial and ethnic minority groups worldwide has prompted an examination of the impact of psychosocial stress on the microbiome. In the vagina, by binding to glucocorticoid receptors in the vaginal wall, stress-induced cortisol is shown to inhibit the deposition of glycogen in a manner which restricts the Lactobacillus population, leading to an increase in proinflammatory cytokines and chemokines and mucosal immunosuppression. ²²² However, whether or not this inflammatory response is solely protective or solely harmful is a subject for debate as it is proposed that people who experience higher levels of stress may have adapted nLDVMs that are able to create acidic environments without reliance upon Lactobacillus.²²³

Risk factors

Risk factors for BV include multiple or new sexual partners, douching,²²⁴ (but not other personal hygienic behaviors), and cigarette smoking.²²⁵ BV has not yet been categorized as an STI because of the absence of a recognized causative organism and lack of a counterpart in males. There is some evidence of BV-related bacteria found in men, but treatment of men has not affected BV in their partners.^{226 227} Despite the lack of STI status, sexual activity of one kind or another has usually been experienced by patients who have BV.^{228 229} For lesbian women, sexual transmission is common; there is a high occurrence of BV and concordance of flora in women who have sex with women.^{230 231} Incident bacterial vaginosis (BV) in women who have sex with women is associated with behaviors that do suggest sexual transmission of BV. One study showed that women in long-term, monogamous, lesbian relationships were also likely to have concordant normal vaginal organisms.²³² When asked about triggers for their BV, women themselves identify a relationship with sexual activity (sex with a regular male or female partner, sex with a new partner, sex with an uncircumsized male, and sex without a condom).²³³ Condom use and estrogen based OCPs may be protective.²³⁴

There is an association between bacterial vaginosis and sexually transmitted infections.²³⁵ One study showed that women with herpes simplex type 2 infection had a 55 % higher risk of having BV than did those who were not infected.²³⁶ There is an increased risk of both gonorrhea and chlamydia in the presence of BV.^{237 238} There is a relationship between HIV and BV: women with BV may be more likely to contract HIV²³⁹ and women with HIV are more likely to have BV and for it to be persistent.^{240 241}A study of HIV positive women in India showed an increased prevalence of BV, Candida, and Trichomonas in the study population, with higher numbers in those with lower CD4 counts.²⁴²

Clinical manifestations and symptoms

Approximately 50% of patients with BV are asymptomatic.²⁴³ Symptoms of BV include an unpleasant, “fishy-smelling” discharge often prominent after intercourse. The discharge is usually off-white, thin, and homogeneous. Dysuria and dyspareunia are rare, and pruritus, erythema, and inflammation are typically absent.²⁴⁴

Diagnosis

History, speculum and pelvic examination, pH, whiff test, and wet mount are essentials of diagnosis. However, health care providers do not always follow these standards. One record review showed that whiff and pH measurements were performed in only 3% of women presenting with complaints. 42% of referring physicians did not perform microscopy, and 54% of visits resulting in medication showed inadequate evaluation of patients.^{245 246} Diagnosis is based on the presence of three of four of Amsel’s criteria (sensitivity >90%):²⁴⁷

Table P-10: Amsel’s criteria for diagnosis of bacterial vaginosis (three of four must be present)²⁴⁸

Clue cells are squamous epithelial cells covered with adherent bacteria, making the margins shaggy, uneven, and “moth-eaten” in appearance. These are the most reliable predictors in the diagnosis of BV.²⁴⁹ To be diagnostic, at least 20% of the epithelial cells on wet mount should be clue cells.

The Nugent test, (gram staining of vaginal secretions), is a reliable but clinically cumbersome method of diagnosis of BV (sensitivity 62-100%) usually utilized in a research setting.²⁵⁰ (See Table P-4: Nugent score table for gram stained vaginal smears for detecting bacterial vaginosis)

Vaginal culture has no role in diagnosis because there are no bacteria that are specific for BV. Although cultures for G. vaginalis are positive in almost all women with symptomatic infection, the organism is detected in up to 50 to 60 percent of healthy asymptomatic women; thus, its presence alone is not diagnostic of BV.²⁵¹

PCR testing and DNA probes have become widely available for clinical use, but in a setting where microscopy is available, in-person evaluation is preferred to be able to detect the presence or absence of lactobacilli, WBCs, clue cells, pH and whiff.²⁵²

Five quantitative PCR assays are available: Max Vaginal Panel (Becton Dickinson), Aptima BV (Hologic), NuSwab VG (LabCorp), OneSwab BV Panel PCR with Lactobacillus Profiling by qPCR (Medical Diagnostic Laboratories), and SureSwab BV (Quest Diagnostics). Two of these assays are FDA cleared (BD Max Vaginal Panel and Aptima BV), and the other three are laboratory-based tests. Self sampling for BV and Candida has been found to be non-inferior to typical collection by a healthcare provider. This practice may alleviate the need for some follow up visits for patients with recurrent BV or to confirm the condition, but should not be relied upon.²⁵³

The following table, thanks to Dr Claire Danby, may help to clarify the choices of tests outside of pH, microscopy, and KOH and whiff testing:

Table P-11 Bacterial Vaginosis: Other diagnostics (from a 2021 lecture)

A Papanicolaou smear is not reliable for diagnosis of BV.²⁵⁴ If cytology suggests a shift in flora, women need standard diagnostic testing with examination, vaginal pH, whiff test and wet mount if symptomatic. Asymptomatic women do not need testing when a shift in flora is picked up on Pap smear.

Differential diagnosis

Other conditions that produce discharge and elevated vaginal pH >4.5 include trichomoniasis, vaginal atrophy, and desquamative inflammatory vaginitis (DIV). They can be distinguished by clinical and microscopy findings. Vaginal inflammation and dyspareunia are hallmarks of trichomoniasis, DIV, and atrophic vaginitis, not seen with BV. Increased parabasal cells are always seen with atrophy and DIV, and are not found with BV. Large numbers of polymorphonuclear leukocytes characterize trichomoniasis, DIV, and sometimes atrophic vaginitis but are not seen with BV. Motile trichomonads seen on microscopy are diagnostic of trichomoniasis.

Complications of bacterial vaginosis

BV is associated with a number of complications in both pregnant and non-pregnant women. It is causally associated with upper genital tract disease including endometritis, postpartum fever and post-hysterectomy cuff cellulitis, and post-abortion infection.^{255 256} BV is a risk factor for acquisition of STIs:²⁵⁷ HIV,²⁵⁸ HSV-2, gonorrhea, and Chlamydia.²⁵⁹ BV is often seen in women with pelvic inflammatory disease (PID), but its role as a risk factor is unclear.²⁶⁰ BV is associated with pregnancy-related complications of premature rupture of the membranes, premature delivery, and post-Cesarean wound infection.²⁶¹ For this reason, treatment for all symptomatic pregnant patients is indicated. The exact nature of the association between BV and adverse pregnancy outcomes is unclear. The vaginal immune system may explain why only a minority of women with BV have adverse pregnancy outcomes. Although all women with BV lack classic signs of inflammation (vaginal erythema, vaginal leukocytes in wet mount), pregnant women with BV have silent evidence of inflammation: markedly elevated vaginal levels of the master pro-inflammatory cytokine IL-1b,²⁶² strongly associated with elevation of another pro-inflammatory cytokine IL-8.²⁶³ Pregnant women who have BV and the presence of Mobiluncus were more likely, in one study, to have lower levels of both IL-1b and Il-8.²⁶⁴ It is hypothesized that the failure to increase IL-8, possibly caused by bacterial virulence factors such as a bacterial protease (sialidase) present with BV, may result in impairment of vaginal epithelial defenses, allowing easier migration of organisms to the upper genital tract.²⁶⁵ Treatment of high risk pregnant women with asymptomatic BV is not proven to improve outcomes.²⁶⁶

Treatment

The established benefits of therapy for BV in non-pregnant women are to relieve vaginal signs and symptoms and to reduce the risk for infectious complications after procedures such as abortion or hysterectomy. Other potential benefits might include a reduction in risk for other infections (e.g., HIV and other STIs). All women who have symptomatic disease should be treated.²⁶⁷ Trials that evaluated the use of anaerobic antimicrobial coverage (i.e., metronidazole) for routine operative prophylaxis before abortion and trials that evaluated this additional coverage for women undergoing hysterectomy demonstrated a substantial reduction in postoperative infectious complications.²⁶⁸ Therefore, treatment of both symptomatic and asymptomatic women who are to undergo pregnancy termination or hysterectomy is recommended. Because treatment of BV may also reduce the risk of acquiring other STIs, including HIV,²⁶⁹ some experts now support the concept of treating all women with BV regardless of presence or absence of symptoms. In the United States, treatment options have consisted of metronidazole or clindamycin, both available in oral and topical preparations. The Sexually Transmitted Infections Treatment Guidelines from the Centers for Disease Control and Prevention (CDC) include:

Table P-12: CDC Recommended treatment regimens for bacterial vaginosis in non-pregnant women²⁷⁰

Table P-13: CDC recommended alternative regimens for bacterial vaginosis in non-pregnant women²⁷¹

Metronidazole therapy

The recommended metronidazole regimens are equally efficacious and metronidazole is the treatment of choice. Metronidazole gel is as effective as oral metronidazole, but the choice of agent is left to patient preference. One randomized trial evaluated the clinical equivalency of intravaginal metronidazole gel 0.75% once daily versus twice daily and demonstrated similar cure rates 1 month after therapy.²⁷²

Most comparative studies using multiple divided-dose oral regimens for one week achieved early rates of clinical cure in excess of 90%, and cure rates (by Amsel’s criteria) of approximately 80% at four weeks.²⁷³ There was a significantly higher short-term cure rate when the initial treatment with metronidazole therapy was extended from seven to 14 days.²⁷⁴ However, long-term cure rates (21 days after completion of therapy) were similar for both treatment regimens.

Side effects of metronidazole include nausea, diarrhea, headache, and metallic taste. The warning regarding Metronidazole and alcohol use (disulfiram-type reaction) is no longer applicable. Metronidazole has been associated with a range of CNS effects which include peripheral neuropathy, aseptic meningitis, ataxia, neurocerebellar toxicity, confusion or diorientation, dysarthria, encephalopathy, seizures, optic neuroathy, and vertigo, with most effects reversible within days to weeks of discontinuation; peripheral neuropathy symptoms may be prolonged.²⁷⁵

Clindamycin therapy

The standard topical vaginal therapy with 2% clindamycin cream (5 g of cream containing 100 mg of clindamycin phosphate) covers a seven-day regimen. Although it may be less effective than the metronidazole regimens,²⁷⁶ it is still recommended. Alternative dosing of 100 mg ovules, 1 intravaginally daily for three days, may be prescribed.

Limited data have been published that compare the clinical or microbiologic equivalencies of this regimen with other regimens. Cure rates do not differ between intravaginal clindamycin cream and ovules.^{277 278}

The main side effect of clindamycin is diarrhea. Pseudomembranous colitis has been reported with both oral and topical clindamycin. Clindamycin cream is oil-based and might weaken latex condoms and diaphragms for 5 days after use.

Increased prevalence of clindamycin-resistant anaerobic bacteria in the vagina is seen post-treatment. 17% of bacterial isolates before therapy versus 53% of isolates after therapy have been reported with clindamycin.²⁷⁹ This effect persisted in most women for at least 90 days after clindamycin treatment. In contrast, increased resistance to metronidazole was not observed in women treated with that drug. The clinical significance of these findings is not yet clear. A study of Gram stain in women who had received metronidazole gel, single-dose clindamycin vaginal cream, or standard clindamycin cream, was performed at baseline and one month after treatment during three different clinical trials performed in a similar manner. In all three treatment groups lactobacilli increased to a similar degree.²⁸⁰

Allergy or intolerance to the recommended therapy

Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole or tinidazole. Intravaginal metronidazole gel can be considered for patients who do not tolerate systemic metronidazole, but patients who are truly allergic to oral metronidazole should not be administered intravaginal metronidazole. Desensitization to metronidazole can be performed by consultation with an allergist, or as outlined in the literature.²⁸¹

Tinidazole and secnidazole therapy

Tinidazole and secnidazole are second-generation nitroimidazoles. Compared to metronidazole, tinidazole has a longer half-life of 12 to 14 hours versus 6 to 7 hours and fewer side effects.²⁸² It is at least as effective as metronidazole, as shown in randomized trials in the United States and elsewhere.²⁸³ A dose of 1 g orally once daily for five days has a slightly higher efficacy and fewer side effects than with shorter course therapy with more medication (tinidazole 2 g orally daily for two days).²⁸⁴ Secnidazole use for treatment of BV has the advantage of one-time dosing. Clinical cure rate of 2 g oral secnidazole was not different from oral metronidazole.²⁸⁵

Treatment during pregnancy

Treatment of symptomatic BV in pregnancy is recommended to relieve symptoms and possibly reduce risks. BV during pregnancy is associated with adverse pregnancy outcomes, including premature rupture of the membranes, preterm labor, preterm birth, intra-amniotic infection, and postpartum endometritis. Treatment may also reduce risk of STIs, including HIV. Although metronidazole crosses the placenta, there has been no evidence of teratogenicity or mutagenic effects in infants. Some experts avoid topical therapy in pregnant women because they believe oral treatment is more effective against potential subclinical upper genital tract infection, but intravaginal clindamycin and metronidazole gel have been shown to be safe in pregnancy. Tinidazole is not recommended for pregnancy.

Table P-14: CDC recommended treatment regimens for bacterial vaginosis in pregnancy²⁸⁷

Treatment of asymptomatic BV among pregnant women at low risk for preterm delivery has not been reported to reduce adverse outcomes of pregnancy. Therefore, routine screening of pregnant people without risk factors is not recommended.

Treatment of bacterial vaginosis in breastfeeding women

Infectious disease expert Jack Sobel recommends using oral Metronidazole 500 mg twice a day for seven days to treat lactating women with symptomatic BV.²⁸⁸ Serum levels received by infants are less than therapeutic infant doses would be and studies have shown no or minimal adverse effects in neonates exposed to this dosing. (Cohort studies have shown possible increased incidence of candidiasis or diarrhea).²⁸⁹ Oral clindamycin use (300 mg twice a day for seven days) is acceptable in breastfeeding women according to The American Academy of Pediatrics (AAP),²⁹⁰ however, the infant should be monitored for diarrhea, candidiasis (thrush, diaper rash) or, rarely, blood in the stool indicating possible antibiotic-associated colitis because of clindamycin’s potential to cause adverse effects on the breastfed infant’s gastrointestinal flora. Infant side effects are less likely with vaginal clindamycin than oral use since only about 30 percent of a vaginal dose is absorbed. Outcome data of maternal metronidazole use has not shown a significant increase in adverse events compared to use of other antimicrobials. Use of vaginal metronidazole has not been studied during breastfeeding. After vaginal administration, plasma levels are less than 2 percent of those after a 500 mg oral dose, so vaginal use of metronidazole during breastfeeding is unlikely to be of concern.²⁹¹ Patients who are given tinidazome or secnidazole should avoid breastfeeding for 24-48 hours.

Treatment of recurrence and relapse in bacterial vaginosis

Recurrence of BV is common and troublesome for women. Cure for BV is reflected in normal pH and wet mount at four weeks after treatment. Since approximately 80% of patients successfully treated with therapy have a recurrence of symptoms within three months, the use of the word “cure” is misleading.²⁹² There is little consensus on best practices to treat recurrent bacterial vaginosis (RBV). CDC Guidelines state that retreatment with oral or vaginal metronidazole or suppressive therapies using a variety of regimens is helpful, but the effectiveness diminishes once treatment is stopped.²⁹³ Recurrence may occur because lactobacilli are unable to reestablish themselves or because pathogenic bacteria are reintroduced or persist.²⁹⁴ More recent studies are focusing on the role of the biofilm in preventing clearing of BV with metronidazole.²⁹⁵ A recent retrospective cohort analysis shows promise: 105 women with RBV were treated with oral nitroimidazole (tinidazole or metronidazole) 500 mg twice a day for 7 days with simultaneous vaginal boric acid 600 mg for 30 days. (It is essential that boric acid never be taken orally because it is poisonous, and it must be kept away from children). Thereafter, they were prescribed twice weekly vaginal metronidazole gel for 5 months followed by a 6 month observation period. Initial treatment was successful in 92/93 patients. Maintenance gel prevented recurrence in 69.6% at 6 months. Long term cure at 12 months was seen in 69% of women. There was a signifiant loss to follow up at 12 months, but these findings certainly warrant further prospective study.²⁹⁶ The concomitant treatment of BV with disruption of the biofilm may be the key to longer symptom-free intervals or possible resolution. Although the anti-fungal effects of vaginal boric acid may prevent some overgrowth of yeast, many of the patients in this last study had to be treated with an anti-fungal, as well.²⁹⁷

 

Treatment of sexual partners

It is difficult to discern relapse from reinfection and to know what role partner colonization might play. It is logical to posit that BV infection is affected by flora of the penile skin. Male circumcision seems to decrease the prevalence of BV in female partners, but does not completely prevent it.²⁹⁸ Previous trials are limited due to many uncontrolled variables. Despite more than 60 years of research looking at the role of male treatment, there are not definitive data to support treatment of male partners.^{299 300} At the same time, there is good evidence that BV is related to sexual transmission in some way. Researchers continue to explore the question of partner treatment to improve outcomes.³⁰¹ Despite BV being common amongst women having sex with women, to date, no female couples have been enrolled in treatment trials.³⁰²

Condom therapy

Reduced rates of recurrence have been documented when male sexual partners used condoms routinely with intercourse, or when the patient remained abstinent.³⁰³ Another report also suggests that condom therapy combined with medication is effective.³⁰⁴

Alternative treatments

Douching

Douching is not advised for treatment of BV. It is associated with an increase in BV secondary to the disruption of the normal vaginal flora.³⁰⁵

Boric acid vaginal acidifying treatment

Vaginal boric acid used alone or other agents that decrease the vaginal pH have not been shown to reduce the risk of BV. As noted above, there is promising evidence that, used in conjunction with long-term suppressive therapy with metronidazole, vaginal boric acid has the utility in the treatment of recurrent BV.

Probiotics

An exhaustive review of the literature by Joseph, et al, showed that there is no evidence, as of yet, to conclusively support using oral or intravaginal probiotics to decrease the incidence or recurrence of BV.³⁰⁶ One study using intravaginal Lactin-V (Lactobacillus crispatus CTV-05),³⁰⁷ more studies are needed. In addition, the use of dietary supplements containing live bacteria or yeast in immunocompromised patients has been shown to result in death in some patients.³⁰⁸

Vaginal microbiome transplantation

Vaginal microbiome transplantation has been studied in only a very limited number of patients and will need more study.³⁰⁹

Epidemiology

In 2016, the World Health Organization (WHO) estimated an incidence of 276 million new cases each year and prevalence of 187 million infected individuals.³¹³ The prevalence of T. vaginalis in the United States is 2.1% among women ages 14-59, and 0.5% among men, based on a nationally representative sample of people who participated in the NHANES (National Health and Nutrition Examination Survey) in 2013-2016:

• Prevalence was 9.6% for African American women, 1.4% for Hispanic women, and 0.8% for non-Hispanic white women.
• For men and women, increasing poverty level, lower educational level, unmarried status, and having been born in the U.S. are associated with T. vaginalis infection.
• For women, younger age at first sex, greater number of sex partners, and a history of chlamydia infection in the past 12 months are associated with T. vaginalis infection.^{314 315}

Etiology

Trichomoniasis is caused by a pear-shaped protozoan with flagellae, Trichomonas vaginalis, that may be located in the cervix and vagina, urethra, and paraurethral glands, as well as in the Bartholin and Skene glands. Unlike Chlamydia and gonorrhea, which require endocervical cells for optimal growth, T. vaginalis is primarily a vaginal pathogen. The entire vaginal surface is at risk, with implications for sampling, detection, and persistence of this protozoan.³¹⁶ Once attached to the vaginal epithelial cell, T. vaginalis raises the vaginal pH and releases cytotoxic substances that cause epithelial breaks and inflammation.³¹⁷ It is usually transmitted by sexual intercourse and is often associated with co-infection with other sexually transmitted diseases. It may be transmitted during penile-vaginal sex or through exchange of infected vaginal fluids or fomites among women who have sex with women.³¹⁸ Although survival on fomites has been reported, fomites have no proven role in transmission of trichomonas.³¹⁹ BV may be a risk factor for trichomoniasis, but the relationship between the two conditions is not well understood. Both vaginitides share the clinical signs of elevated pH and positive amine test. Many studies of BV used only a wet mount to exclude trichomonas, possibly resulting in under-estimation of trichomoniasis.

Clinical presentation

The vast majority of women have no symptoms at all: no itching, vaginal discharge, or odor.³²⁰ Asymptomatic carriage can exist for prolonged periods of time, making it impossible to ascertain the source of the infection. When symptoms develop, the typical presentation is a diffuse, malodorous vaginal discharge rather than itching. The classic green and frothy discharge is seen in about 10 % of culture proven infections.³²¹ Punctate hemorrhages in the vaginal and cervical epithelium (strawberry spots) may be visible, but are present in only two percent of cases.³²² Dysuria and frequency are present since the urethra is infected in the majority of women. Dyspareunia may also be present and post-coital bleeding may occur.

Complications

Trichomoniasis is often associated with other STIs, and may contribute to the development of pelvic inflammatory disease.³²³ It appears to increase the risk of herpes and human immunodeficiency virus ^{324 325} T. vaginalis has been found to double the risk of persistent human papilloma virus infection³²⁶ and increase the risk of cervical neoplasia.³²⁷ It is also a risk for post-hysterectomy cellulitis and tubal infertility. Trichomoniasis is associated with premature rupture of the membranes and premature delivery.³²⁸ The pregnancy-related complications, however, have not been reduced by treatment of asymptomatic infection.³²⁹

Diagnosis

As with Candida, bacterial vaginosis or any vaginitis, trichomoniasis cannot be diagnosed by history, signs, or symptoms alone. The elevated vaginal pH >4.5 and increased PMNs frequently noted are not diagnostic. Testing in females is more effective when vaginal secretions are used. With males, it is necessary to use urine samples. Males should be tested with culture, NAAT/PCR, or rapid tests designed for urine samples.

pH and wet mount

Identification of the motile trichomonads on wet mount has long been standard practice. If trichomonads are clearly identified on wet mount, no further testing is needed, although testing for other STIs should be offered.

The wet mount must be performed within 10-20 minutes of obtaining the sample, or motility is lost. The poor sensitivity of wet mount (60-70%) and the time requirements of culture have hindered accurate diagnosis over the years. The CDC recommends adjunctive testing when T. vaginalis is suspected but not seen on wet mount.³³⁰

Other testing options

Culture

Before the development of NAATs (Nucleic Acid Amplification Tests), culture of vaginal secretions on Diamond’s medium, with its sensitivity of up to 95% and specificity of greater than 95%, was considered the gold standard for diagnosing trichomoniasis. However, the seven day wait for results and high cost now make culture desirable only in the case of pH>4.5 with increased WBCs on wet mount with no visible trichomonads, without availability of other testing.³³¹ As the culture on Diamond’s medium was prone to contamination, another culture: InPouch system from BioMed Diagnostics was developed, using a two-chambered bag with the same efficacy as Diamond’s medium.³³² However, molecular testing, with its aim of faster results, ease of use, and lower cost has now become the diagnostic tool of choice.³³³

Nucleic acid amplification tests/PCR

NAAT/PCR testing for T. vaginalis has high sensitivity and specificity and has become the gold standard now. The Aptima T.vaginalis assay from Hologic has a reported sensitivity and specificity range of 95-100% in all specimen categories (secretions and urine) and is FDA approved. When chlamydia and gonorrhea testing is desired, a separate Aptima assay is required, e.g. Aptima Combo 2. ³³⁴

Other tests have also been developed, not all FDA approved. The BD MAX vaginal panel, which is FDA approved, also tests for bacterial vaginosis and candidiasis. Amplicor (Roche) tests for T. vaginalis, N. gonorrhoeae, and C. trachomatis with a sensitivity of 88-97% and specificity of 98-99%. NuSwab VG (LabCorp) is a nucleic acid amplification single specimen assay for the detection of trichomoniasis, bacterial vaginosis, and vulvovaginal candidiasis.³³⁵

Rapid antigen and DNA hybridization probes

Rapid diagnostic kits using nucleic acid probes and monoclonal antibodies are changing the landscape of T. vaginalis testing. An unamplified RNA test (Affirm VP111; Becton Dickinson, Sparks, Maryland) is commercially available with a reported sensitivity of 80-90%, and a specificity of 99% for T. vaginalis compared with wet mount.³³⁶ It is also more sensitive than culture.³³⁷ Affirm requires 45 minutes to perform. The rapid antigen test (OSOM TV; Genzyme Diagnostics, Cambridge, Massachusetts), developed in 2003, is a point-of care, test-strip device that detects T. vaginalis membrane proteins in approximately ten minutes. The test has a sensitivity (83-90%) and specificity (98.8%) similar to culture.³³⁸ Both tests are performed on vaginal secretions.

Cervical cytology

The conventional Pap smear has a sensitivity of 51-63% and a common false positive rate of 7%,³³⁹ making it unacceptable for diagnosis because of its poor predictive value in a low prevalence population.³⁴⁰

Although liquid-based cytology has shown a low sensitivity (61), it has a high specificity (99%) and high predictive value (96.4%),³⁴¹ leading some experts³⁴² to believe that treatment of asymptomatic women with trichomonads noted on liquid based cytology is a reasonable approach. We feel that, especially in low-prevalence settings, a Pap smear by any technology giving a possibly false positive result for trichomonas, does not justify informing a patient that she has a sexually transmitted infection. Rather, the finding of possible trichomonads on Pap warrants confirmation by clinical evaluation with wet mount and culture, PCR testing, or rapid test.

Treatment

Treatment is indicated in all non-pregnant women diagnosed with trichomonas vaginitis, even if asymptomatic. Without treatment, up to one-third become symptomatic within six months. They continue to transmit the infection to sexual partners while untreated.³⁴³

For decades, effective treatment of trichomoniasis relied on the use of the 5-nitroimidazole drug, metronidazole. In 2006, the FDA approved another nitroimidazole, tinidazole for the treatment of T.vaginalis. The efficacy of the nitroimidazoles in curing 90-95% of trichomoniasis is well established, and most strains of T. vaginalis are highly susceptible to the drugs.³⁴⁴ Tinidazole is more expensive than metronidazole, reaches higher levels in serum and the genitourinary tract, has a longer half-life than metronidazole (12.5 hours versus 7.3 hours), and has fewer gastrointestinal side effects. Side effects to metronidazole include nausea, vomiting, headache, metallic taste, and dizziness. Intravaginal metronidazole gel does not reach therapeutic levels in the urethra and perivaginal glands. Because it is less efficacious than oral metronidazole, it is not recommended.³⁴⁵

Cure rates with medications other than the nitroimidazoles are so low that patients with allergy to metronidazole or tinidazole are best referred to an allergist for what is highly effective desensitization.³⁴⁶

Patients are no longer advised to avoid consuming alcohol during treatment with metronidazole or tinidazole because of the possibility of a disulfiram-like (Antabuse) effect.³⁴⁷

There are no studies on how long trichomonads remain viable after treatment is initiated or completed. Patients need education to avoid intercourse until they and their partners have completed treatment and are asymptomatic, about a week.

The CDC advises repeat testing of sexually active women in three months or at the time of their next visit.

Table P-15: CDC recommended regimens³⁴⁸for trichomoniasis in non-pregnant women

Management of sexual partners

Sex partners of patients with T. vaginalis should be treated. Maximal cure rates in affected women are achieved when their male sexual partners are treated simultaneously.³⁴⁹ Data regarding female partners is not available, but sexual transmission of trichomonas between women is reported.³⁵⁰

Women should be instructed to avoid sex until they and their sex partners are cured (i.e., when therapy has been completed and patient and partner(s) are asymptomatic) or a follow up test at 3 months is negative.

Pregnancy

Symptomatic women in pregnancy should be tested and treated because trichomoniasis is associated with adverse pregnancy outcomes: premature rupture of membranes, preterm delivery, and delivery of small for gestational age babies. There is no standard at this time for routine screening in pregnancy.

Treatment of sexual partners of pregnant women is always indicated. In the untreated asymptomatic woman, re-infection of treated partners of untreated women can be minimized by abstinence or condom use.

Metronidazole 500 mg orally twice a day for seven days is the drug of choice for treatment of symptomatic trichomoniasis in pregnancy.³⁵¹³⁵²

Over the years, clinicians have avoided use of metronidazole in the first trimester because the drug is mutagenic in bacteria and carcinogenic in mice. In humans, it crosses the placenta and has a theoretical potential for teratogenicity. Meta-analysis has not found any relationship between metronidazole exposure during the first trimester of pregnancy and birth defects.³⁵³ The Centers for Disease Control and Prevention no longer discourage the use of metronidazole in the first trimester. Vaginal metronidazole gel is not recommended because it does not adequately treat trichomoniasis. Tinidazole is not recommended in pregnancy.

Table P-16: CDC recommended regimen for symptomatic trichomoniasis in pregnant women

 

Breastfeeding

Use of metronidazole in breast-feeding mothers has caused concern because of the association with carcinogenesis in rodents. There are no human data to show an association between metronidazole and cancer,³⁵⁴ and maternal metronidazole use has not shown a significant increase in adverse events compared to use of other antimicrobials, although one study found a non-significant trend toward more loose stools in infants.³⁵⁵ With maternal oral therapy, breastfed infants receive metronidazole in doses that are lower than those used to treat infections among infants. If it is necessary to use oral tinidizole 2 g orally once, the patient should abstain from breastfeeding for 72 hours.³⁵⁶

Allergy to metronidazole

Desensitization to metronidazole can be performed by consultation with an allergist, or as outlined in the literature.³⁵⁷

Imidazole-resistant trichomonas vaginalis or treatment failure

If treatment failure occurs in a woman after completing a regimen of metronidazole 500 mg 2 times a day for 7 days and she has been reexposed to an untreated partner, a repeat course of the same regimen is recommended. If no re-exposure has occurred, she should be treated with metronidazole or tinidazole 2 g once daily for 7 days.³⁵⁸

The CDC will provide a special kit and guidance for performing drug-resistance testing if necessary. (https://www.cdc.gov/laboratory/specimen-submission/detail.html?CDCTestCode=CDC-10239).

Table P-17: CDC recommended treatment regimens³⁵⁹ in imidazole-resistant Trichomonas vaginalis

These regimens can be effective in patients with low levels of metronidazole resistance.

Therapeutic options include maximum tolerated doses of metronidazole, or preferably tinidazole (2 to 4 g daily in divided doses) for 14 days. Patients with high-level metronidazole resistance are usually successfully treated by prolonged and high-level tinidazole therapy, although cross-resistance to tinidazole is frequently reported.³⁶⁰ The optimal dose has not been established.

Epidemiology

Between 27% to 84% of postmenopausal women will experience symptoms of GSM.^{389 390 391 392 393 394} Unlike other menopausal symptoms, such as hot flashes and sleep disturbances, that usually improve over time, vulvovaginal atrophy (VVA) is generally progressive in the absence of effective therapy. Vulvovaginal symptoms associated with estrogen deficiency can also occur during the female reproductive years. Premenopausal women can experience symptoms with the use of hormonal contraceptives, anticholinergic or chemotherapeutic medications, postpartum/breastfeeding, or inflammatory conditions. In a cohort of breast cancer survivors, vaginal dryness was present in 39.4% of the premenopausal patients.³⁹⁵

Pathophysiology

In the menopausal woman, an approximately 95% decline in estradiol levels³⁹⁶ leads to several gradual and persistent changes in the female genitals, where there is a high concentration of estrogen receptors. Estrogen maintains urogenital health through vascular, cellular, and structural mechanisms.

In GSM:

• The superficial vaginal epithelial layer thins, loses its elasticity, and can become friable
• Local blood supply decreases
• Glycogen and collagen content in the superficial epithelium wanes
• There is a change in vaginal microbiome as the glycogen that supports lactobacilli decreases
• This leads to an elevated vaginal pH
• Rugae flatten and disappear
• The vaginal canal shortens, narrows, becomes less distensible and can develop strictures
• As blood flow diminishes, secretions are lessened, and onset of lubrication during sexual stimulation is delayed.^{397 398}

Etiology

Vulvovaginal atrophy can be caused by any condition or medication that results in a hypoestrogenic state:

• Natural menopause³⁹⁹
• Primary ovarian insufficiency
• Postpartum or breastfeeding
• Bilateral oophorectomy
• Hypothalamic amenorrhea and hypothalamic disease
• Use of anti-estrogenic medications: SERMS (although tamoxifen has estrogen agonist effects on the uterus and vagina),⁴⁰⁰ aromatase inhibitors, danazol, medroxyprogesterone acetate, gonadotropin releasing hormone agonists: leuprolide, nafarelin, goserelin
• Sustained use of some oral contraceptive pills (20 mcg of ethinylestradiol (EE)/100 mcg of levonorgestrel and 15 mcg of EE/60 mcg of gestodene)⁴⁰¹
• Oral contraceptive pills with low levels of estrogen that ALSO contain drospirenone, desogestrel, or norgestimate. Testosterone contributes to lubrication in the vagina so birth control pills that lower a women’s testosterone levels (directly, by decreasing ovarian production or indirectly, by increasing SHBG) can contribute to vaginal dryness.
• Elevated prolactin with secondary reduction in ovarian secretion of estrogen
• Radiation, chemotherapy, or surgery that can lead to ovarian failure, including uterine artery embolization and uterine ablation
• Diminished androgen levels may contribute⁴⁰²
• Other factors that might promote atrophy of vaginal tissue, including tobacco use, cessation of coital activity, never having had a vaginal delivery, and vaginal surgery.⁴⁰³

Clinical manifestations

The symptoms of GSM may include sensations of vulvovaginal dryness, burning, vaginal discharge, dysuria, and dyspareunia, especially in sexually active women. While mild to moderate atrophy (GSM) may be asymptomatic or cause no discomfort for some women,⁴⁰⁴ it often worsens in the postmenopausal years. Symptoms advance from slight decrease in lubrication with sexual stimulation to marked dryness (75%), burning and/or pruritus, pain (15%), and dyspareunia (38%). Yellow-brown discharge and spotting, especially post-coitally, can occur when atrophy is severe. Irritative urinary tract symptoms such as frequency, urgency, dysuria, and hematuria are also part of GSM.⁴⁰⁵

It is important to remember that hormonal changes may not adequately explain postmenopausal dyspareunia, the predominant symptom attributed to the effect of low estrogen levels on female genitalia. Pain is also influenced by cognitive, affective, and dyadic factors. One study showed that, in comparison with hormone levels, cognitive-emotional variables (e.g., catastrophization, depression, anxiety) were found to be stronger predictors of pain than hormonal levels.⁴⁰⁶ On the other hand, the vaginal maturation index (VMI) assessment on microscopic wet mount showing a preponderance of parabasal cells and an absence of lactobacilli, associated with an elevated pH, is a significant predictor of both induced and intercourse-related vestibular pain.⁴⁰⁷

Diagnosis

History

An inquiry about symptoms of GSM in all peri and post menopausal women should be part of a routine review of systems. The EMPOWER survey of 2017 found that, in women who had never used any treatment, almost three quarters had never discussed their symptoms with a healthcare provider.⁴⁰⁸ As previously stated, the main reason for this reticence was an assumption that GSM was simply a natural part of aging and did not require remedy. Others were embarrassed to bring the topic up or did not think it was an appropriate topic to discuss with a health care provider. Women also lack basic information about GSM and possible remedies and would therefore benefit from routine queries and written handouts.⁴⁰⁹

Symptoms similar to atrophy (VVA associated with GSM) may be reported by postmenopausal women with other conditions: vulvovaginal infection, foreign body in the vagina, contact or allergic reaction, vulvar dermatoses, benign or malignant tumors, medical conditions such as diabetes, and psychological causes.⁴¹⁰ In women of reproductive age, the clinician may not think of atrophy as a potential problem.

Annotation B (B: The patient’s history ) covers the details of taking a history for any vulvovaginal complaint. In the case of suspected GSM, the history should especially include partner relationship(s), current and past sexual activity, urinary symptoms, interventions tried, including home remedies, treatment goals (comfort, sexual activity), and level of distress with symptoms. If a woman has a history of cancer, details of site, hormone dependence, past and current cancer treatment, age at diagnosis and current age, type of menopause, etc, should be detailed. Discussion of radiation is included in Annotation O. Vaginal epithelium. Click radiation (LINK).

Physical examination

Signs of GSM observed during evaluation of the vulva and vagina vary with the degree of atrophy. With early stages, the epithelium of the vestibule is thin and dry. The vagina may appear mildly erythematous. With progression, there is diminished pubic hair and loss of the fat pad of the mons pubis. The labia majora become pendulous and the minora flatten and are less distinct. The prepuce may decrease in size, uncovering the clitoris in some women, and making it appear larger.⁴¹¹ As atrophic change progresses, the clitoris may recede and, in some cases, become completely flush with the surrounding tissue. As time goes on, vulvar and vestibular tissues appear thin, dry, and pale; the vestibule may be tender to touch, yielding a positive Q-tip test in a patient who does not have vulvodynia, but rather vulvovaginal atrophy (GSM).

 

A urethral caruncle may be seen, manifesting, under estrogen deprivation, as a dark red, fleshy outgrowth representing mild prolapse of the distal urethral mucosa. These lesions may be painful and may be associated with dysuria or spotting. Caruncles are usually small, but can grow to 1-2 cm in diameter. (Atlas of Vulvar Disorders)

The severely atrophic vagina is poorly distensible, short, and narrow. The vaginal epithelium is smooth and dry, and may display color changes from erythema to pallor. It is easily injured by a speculum which may cause petechiae and bleeding. Some women develop a brown or yellow discharge. (Choosing an appropriate vaginal speculum is important for the patient’s comfort and to accomplish a successful exam. Use of a narrow Pederson or pediatric vaginal speculum with lubricant may be best. If well tolerated, the patient should inform the next clinician who sees her about what works for her. If not tolerated, the clinician may have to stop the exam). With advanced atrophy (GSM), the fornices may be obliterated, making the cervix flush with the vault. In some cases, use of even the thinnest Pederson or pediatric speculum may be impossible. (Application of 4% aqueous lidocaine for ten minutes prior to exam may be helpful). In these cases, it still may be possible to insert a Q-tip for pH, wet prep, and other testing.

A woman’s symptoms do not always correlate with physical findings. For example, a woman who is not sexually active may have few complaints, despite signs of advanced genitourinary atrophy on examination. Women who are not sexually active may, however, be bothered by other symptoms related to GSM, including vulvar discomfort with exercise or dysuria. In the absence of complaint, atrophic changes noted on exam do not necessarily require treatment.

Laboratory/point of care testing

Diagnosis of VVA/GSM is primarily a clinical one.

Natural menopause occurs with the final menstrual period, which is known with certainty only in retrospect one year or more after the event. An adequate independent biological marker for menopause does not exist, and there is no role for serial measurements of serum estradiol or follicle-stimulating hormone (FSH) levels for most women.

A single hormone value of low estrogen or elevated FSH may be misleading, since hormonal variation is characteristic of the perimenopausal years. In the late menopausal transition, fluctuations in serum concentrations of FSH and estradiol may be quite striking; high FSH and low estradiol values may be suggestive of menopause, but soon thereafter, one may see that FSH and estradiol have returned to the normal premenopausal range.⁴¹² Therefore, a single serum FSH value in the postmenopausal range, even with undetectable estradiol (and inhibin) levels does not provide reliable evidence that menopause has occurred.⁴¹³

The vaginal maturation index (VMI), described in a study by Meisels in 1966⁴¹⁴ has been very helpful in accurately diagnosing vaginal atrophy as well as ruling out other conditions that may mimic it. His studies defined estrogenization norms and showed that a cytologic measure of vaginal epithelial maturity reflected the effect of circulating estrogens, androgens, and progestogens.⁴¹⁵ Lindau, et al, replicated Meisels’ work in 2017. Interestingly, while the norms established by Meisels held true proportionately, vaginal estrogenization was higher in every age group than reported in the 1960’s study and previous hormone therapy use, obesity, and African American race were each independently associated with a higher MVI. Lindau’s group points out that rates of obesity in US women have increased from 15.0% in 1960 to 35% in 2012,^{416 417} and they theorized that increased exposure to environmental estrogens might also account for increased maturation values in contemporary women. Lindau’s study confirmed that low maturation value was associated with vaginal dryness during sexual vaginal penetration,⁴¹⁸ however, they found that, in their cohorts, “there was not an age-related decline in vaginal estrogenization after menopause and that post meopause, half of all women will exhibit vaginal atrophy, but half will not.”

Hypoestrogenism induces a decline in the vaginal epithelium glycogen level, which is the substrate for lactobacilli. The consequent reduction of lactobacilli leads to an increase in the pH and a shift in not only the proportion of superficial, intermediate and parabasal cells, but a possible shift in the resident microbiota. The decrease in lactobacilli and increase in bacterial diversity, including more enteric bacteria, can result in a brown or yellow, and sometimes malodorous vaginal discharge.

Vaginal pH testing and microscopy, essential to determine the VMI and to diagnose vaginal infections or imbalances in microbiome, are invaluable aids not only to diagnosis of genitourinary atrophy but also to evaluation of treatment. Vaginal pH may be as high a 7.0 in postmenopausal women not on estrogen therapy, but will revert to lower levels (4.5-5.0) in women using vaginal estrogen.⁴¹⁹

The wet mount may show greater than one white blood cell per epithelial cell, and will show reduction in mature squamous epithelial cells, the presence of immature parabasal cells, and reduction or loss of lactobacilli. The pH and microscopy synopsis illustration in Microscopy pH and Microscopy Synopsis Illustration shows that changes in the post menopausal wet mount are normal but also support the patient’s atrophy-related complaints.

Overgrowth of other flora, usually bacterial, may or may not be present. (Candidiasis and bacterial vaginosis are rare in postmenopausal women not using estrogen).⁴²⁰ The wet mount of atrophy (GSM) is sometimes identical to that of desquamative inflammatory vaginitis (DIV) or vaginal lichen planus, although the wet prep in the case of GSM tends to be less cellular than that of DIV, usually showing few WBC’s and a preponderance of parabasal cells. Please see Box #5 in the Microscopy Table of conditions associated with an elevated pH to understand the process of diagnosis for VVA versus DIV. Elevated pH Microscopy Table: Box 5 illustrations A trial of adequate local estrogen is essential to differentiate these conditions in cases where there is a reason for low estrogen.⁴²¹

Possible adjunctive point of care testing includes the Vaginal Health Index (VHI) in which only a vaginal pH is done and is included in a scoring system that clinically measures elasticity of tissue, fluid volume (pooling or secretions), epithelial integrity, and moisture (coating).⁴²²

Table P-19 Vaginal Health Index ⁴²³

This assessment system, used originally for research, can be helpful in conceptualizing the signs of atrophy the clinican should look for.

A 2022 study attempted to find a tool for direct and objective measurement of vaginal moisture. Using a calibrated filter paper similar to the opthalmic Schirmer test for eye moisture, a “modified Schirmer test” was found to be valuable in assessing the degree of vaginal dryness in study and control patients and correlated well with vaginal pH of patients with atrophy, the VHI score and the Visual Analogue Score (VAS) of dryness during intercourse.⁴²⁴ The use of pH and microscopy, which identifies pathogens and imbalances in the microbiome as well as revealing the vaginal maturation index (VMI), is essential in diagnosing all vulvovaginal disorders and continues to be the gold standard in the diagnosis of vaginal atrophy.⁴²⁵ Clues from the physical exam and from the pH, KOH and wet mount, on both first assessment and follow up visits, guide the need for further testing.

Pap smears and vaginal atrophy

Nuclear enlargement seen in atrophic epithelial cells represents one of the criteria for atypical squamous cells (ASC) and low grade squamous epithelial lesions (LGSIL), leading to an abnormal Pap smear.⁴²⁶ For this reason, a Pap with LGSIL can be followed in a woman who is negative for high risk HPV. Adequate local estrogen may be recommended prior to cytologic follow-up.

Differential diagnosis

GSM in the postmenopausal woman may accompany and worsen any vulvovaginal complaint. It is common, for example, to see a postmenopausal woman with symptoms of lichen sclerosus and low estrogen, requiring treatment for both. Symptoms from an over-the counter irritant such as witch hazel, benzocaine topical anesthetics, or aloe that she has applied for relief may be contributing factors to the clinical picture.

Vulvovaginal atrophy (VVA) of GSM may masquerade as:

• Vulvovaginal infection (See sections on Candida, BV, Trichomonas, DIV)
• Foreign body in the vagina
• Contact or allergic reaction
• Vulvar dermatoses: lichen sclerosus, lichen planus (Atlas of Vulvar Disorders)
• Vaginal lichen planus (Annotation N and O)
• Benign or malignant tumors. Cervical, vaginal, and upper tract cancers must be ruled out if vaginal bleeding is a complaint.
• Medical conditions such as diabetes
• Psychological causes
• Vulvodynia
• Any condition causing troublesome vulvovaginal symptoms.

 

Treatment

Treatment of GSM is aimed at alleviation of symptoms by reversing atrophic vulvovaginal changes. For the woman with GSM, after excluding other causes of her symptoms, treatment can be approached systematically. Symptom reduction may take 1 to 3 months, and continued therapy is generally required because symptoms are likely to recur on cessation of treatment. It is important to emphasize this point with patients, who often expect a “quick fix” and may discontinue therapy once tissue integrity is restored. Data on symptom recurrence, however, is lacking.

Although women receiving systemic hormone therapy are less likely to experience VVA and sexual complaints,⁴²⁷ systemic therapy may be inadequate for vulvovaginal comfort in some patients.⁴²⁸ A variety of treatment modalities exists. These include ongoing sexual activity, lubricants, moisturizers, vaginal estrogens, vaginal androgen, pelvic floor physical therapy, vaginal dilators, vaginal laser, topical lidocaine, and systemic androgens, SERMS, and estrogen. Herbal products appear to be ineffective for the treatment of GSM.⁴²⁹

Non-hormonal therapies

Although less effective than hormonal treatments, some women and physicians prefer non-hormonal therapies (moisturizers and lubricants) as the first approach to alleviate vulvovaginal symptoms related to menopause. Moisturizers and lubricants are over-the-counter products with FDA approval as “cosmetics.” They may aid with symptoms but do not reverse atrophic vaginal changes.

Lubricants

Lubricants are temporary measures that may relieve vaginal dryness and minimize friction and irritation for both partners’ genitals during foreplay or penetrative sex. Lubricants have a short duration of action and therefore must be applied frequently. Lubricants can be in liquid or gel form: water-based, oil-based, or silicone-based. In general, water-soluble lubricants are associated with fewer genital side effects than silicone lubricants.^{430 431} Women with vulvovaginal problems should avoid lubricants that contain perfumes, flavors, or warming ingredients.

Decrease in lubrication in postmenopausal women is directly tied to a reduction in systemic and local estrogen. Decreased lubrication in the premenopausal woman can arise from breastfeeding and medications including antihistamines, OCPs, progesten only pills, decongestants, anticholinergics/antimuscarinics, GnRH agonists, SSRIs, chemotherapy, etc. Emotional stressors (job, money, relationships) can also interfere with arousal and lubrications. Older women tend to use lubricants to alleviate the discomfort of VVA, whereas younger women tend to use lubricants to enhance sexual experience.⁴³²

Table P-20: Lubricants: personal preference⁴³³

Water based lubricants are often preferred for their ease of use, but experimentation may be necessary to avoid irritation. Preference should be given to lubricants that have a pH and osmolality similar to that of the vagina. The higher the osmolality of the lubricant, the higher the potential to cause irritation of the mucosa and tissue damage.⁴³⁴ The WHO recommends using a lubricant with a pH of 4.5 (women) and an osmolality below 1200 mOsm/kg.^{435 436}

Table P-21: Osmolality of water based lubricants

Lubricants and fertility

Lubricants may affect sperm integrity and function, thereby decreasing fertilization potential. Motility is significantly decreased by saliva, olive oil, and KY jelly but not by baby oil.⁴³⁷ In a recent study, Markham, et al concluded that with the exception of egg white, which appeared to be a safe option for couples trying to conceive, all lubricants caused significant (P<0.001) reductions in sperm forward progression compared with untreated controls.⁴³⁸ Comparisons of the commercially available lubricants revealed statistically significant differences in forward progression motility: Pre-Seed was superior to Optilube (P<0.001) and to Yes Baby (P<0.001) at 2-4 hours after exposure.⁴³⁹

An earlier study showed that motility was significantly decreased by FemGlide, Replens, and Astroglide, but not by Pre-Seed.⁴⁴⁰ Sperm chromatin integrity is significantly decreased by KY-jelly and FemGlide, but not by Pre-Seed. ⁴⁴¹

Table P-22: pH and osmolality of lubricants and sperm ⁴⁴²

Click here to see table

Lubricants and condoms

It is noteworthy that oil-based lubricants can erode condoms; however, most brands of water-based and silicone-based lubricants are latex-safe and condom compatible. For example, the silicon lubricant, Uberlube, is compatible with natural rubber latex and polyisoprene condoms. Uberlube is not compatible with polyurethane condoms. Patients should not use products made with oil (cooking, baby, coconut, mineral, etc) as lubricants for latex condoms. The oil weakens the material the condom is made from and can cause the condom to break. Polyisoprene in non-latex condoms reacts to oil-based lubricants in the same way latex does. Polyurethane condoms, however, are safe to use with oil-based lubes.

Lubricants and parabens

Parabens are common preservatives that have been used in the cosmetic and food industry and are found in some lubricants.⁴⁴³ They are known to have anti-bacterial and anti-fungal properties. Any product with ‘paraben’ as a suffix contains parabens. KY jelly and Replens contain methylparaben (a type of paraben) and Astroglide contains methyl and propyl paraben plus propylene glycol.

Personal-care products are significant contributors to paraben exposure. Berger, et al. found that adolescent girls who wear make-up daily had a 20-fold increase in propylparaben in their urine compared to those who rarely wear make-up.⁴⁴⁴ This suggests that parabens are absorbed systemically from topical use. Parabens are weakly estrogenic and there is concern that they present a risk, as they have been found in human breast cancer tumors.⁴⁴⁵ Parabens are also thought to affect the mechanism of cell turnover, making an association with carcinogenesis theoretically possible.⁴⁴⁶

Lubricants and glycerin

Glycerin is widely used in medical, pharmaceutical, and personal care products, including lubricants. Typically added to promote lubrication, glycerin is used to reduce the loss of moisture. In some patients it may cause dryness. Glycerin is a metabolic byproduct of sugar so it may promote yeast infections.⁴⁴⁷ Glycerin is also thought to damage the flagellar membrane in sperm and thus to be the potential causative agent in decreasing sperm motility.

Organic lubricants

Organic approaches to lubrication include products free of petrochemicals, parabens, and fragrance. The organic ingredients are infused in some cases with flowers and herbs. Water based formulas include aloe vera, agar agar and xantham gum. Examples included Emerita® and Me Again®. It is important to remember that natural substances such as aloe and hyaluronic acid can still act as irritants.

Lubricant recommendations

Based on informaton about pH, osmolality, ingredients, effects on condoms and diaphragms, and sperm influences, our recommendation for a lubricant for premenopausal patients with vaginal dryness who are attempting pregnancy is Pre-Seed.

As for postmenopausal patients, these are personal products and trial and error is sometimes necessary. The authors have received positive feedback from colleagues and patients about the use of Uberlube. Uberlube is pure silicone with a trace amount of vitamin E. Uberlube uses no animal products, is vegan friendly, has no glycerin, no parabens, no scents, and no flavors. It is anhydrous, so osmolality has not been studied. Uberlube, is compatible with natural rubber latex and polyisoprene condoms. Uberlube is not compatible with polyurethane condoms.

Moisturizers

Another non-hormonal approach to some aspects of GSM is the use of vaginal moisturizers. Without sustaining levels of estrogen, vaginal fluid secretion decreases from 3-4 g/4 hours to 1.7 g/4 hours.⁴⁴⁸ This decrease results in tissue drying. Although topical estrogen in the form of creams, tablets, time-release vaginal rings, etc, restores the vaginal maturation index to the pre-menopausal picture and relieves dryness and dyspareunia, many women do not want to use hormones or have been advised not to.

Unlike lubricants, whose actions are short lived and are best used in concert with sexual activity, vaginal moisturizers are longer lasting and act as an aid to day-to-day comfort, irrespective of the timing of sexual activity. Moisturizers are designed to adhere to the vaginal mucosa, thereby promoting rehydration and mimicking normal lubrication.⁴⁴⁹ These products maintain tissue integrity, elasticity, and pliability and should be used regularly (daily to every three days). The goal of use is to reduce daily symptoms of GSM as well as to decrease dyspareunia.

Moisturizers contain water as well as emollients and preservatives. Additional additives may include perfumes, flavors, spermicides, dyes, and warming agents, any of which can be irritating to aging vulvovaginal tissue. Some moisturizers contain propylene glycol, aloe (natural, but still sensitizing to some), or chlorhexidine–all known irritants. Patients may need to try different formulations to identify the product that is best for them.

A well-known moisturizer is Replens®, a bioadhesive polymer containing purified water, glycerin, mineral oil, polycarbophil, carbopol 974P, hydrogenated palm oil, glyceride, and sorbic acid. It binds to the vaginal epithelium, releasing purified water to form a moist film over the vaginal tissue. For most women, moisturization is maintained if the product is used on a regular schedule of every two to three days; Replens® does not need to be applied just before intercourse. With ongoing use, some women note the build-up of polymer residue as white, cotton wool-like material in the vagina. Replens was originally reported to reverse atrophy (GSM), but these results came into question when it was reported that it caused no change in the maturation index or nuclear area. ⁴⁵⁰

Other vaginal moisturizers include RepHresh, Feminease, Luvena, Silken Secret, KY SILK E, and Me Again. An internet search for vaginal moisturizers turns up many additional products, including products infused with CBD.⁴⁵¹

A new class of moisturizers utilizing hyaluronic acid are now available including Revaree and Hyalo GYN. Hyaluronic acid is a natural polysaccharide in the skin, connective tissue, and eyes, and works by binding to water to retain moisture. It is added to many commercial skin care and wound-healing products because of its purported effect of drawing moisture to wherever it is applied. There are several small head-to-head trials that show products with hyaluronic acid provide comparable efficacy to estrogen-based treatments with vaginal dryness and dysparunia as the primary end points.⁴⁵² A recent prospective, randomized study compared application of intravaginal 1% estradiol cream with intravaginal Vagisan, a hormone-free oil-in-water emulsion (cream), certified as class IIb medical device for intra- and extra-vaginal use (CE 0483) with a lipid content of 23%, a pH adjusted to 4.5 with lactic acid and an osmolality of 374 mOsm/kg, which is in accordance with the WHO’s recommendation of < 380 mOsm/kg for personal lubricants.⁴⁵³ Results showed that the non-hormonal cream was “not inferior” to the estradiol cream and complaints of side effects were about the same in both groups.

There are few published reports on the safety, efficacy, and irritation potential of vaginal lubricants and moisturizers. Women with concerns can test products on a small patch of skin for 24 hours before using them intravaginally. If the product they test successfully on the skin still causes irritation in the vagina, a woman can switch to an iso-osmolar, propylene glycol-free or silicone-based product. Cost of these products p-20varies considerably and will be a consideration for some users.

Table P-23: Vaginal moisturizers

Click here to see table

Local vaginal estrogen treatment

While effective for many menopausal complaints, systemic estrogen, even at higher doses, fails to relieve vulvovaginal symptoms in 10% to 25% of women.⁴⁵⁴ Some oral estrogens (Premarin, Estrace) are FDA approved for the treatment of VVA. Among transdermal estrogen creams and gels, only Estrogel 0.06% is approved for the indication.

Vaginal atrophy (GSM) is effectively treated with local estrogen, either intravaginally or topically at the introitus. Formulations include vaginal creams, a vaginal ring with time-released medication, or vaginal tablets. Much lower doses of estrogen than those used systemically, applied directly to the vagina, result in improvement in GSM with minimal elevation of serum estradiol levels.⁴⁵⁵ Local vaginal therapy is therefore preferred over systemic estrogen for this indication.⁴⁵⁶

There are multiple vaginal estrogen products. A Cochrane review of trials on over two thousand women concluded that conjugated estrogen vaginal cream, estradiol vaginal tablets or the estradiol vaginal ring were all equally effective for relief of symptoms.⁴⁵⁷ Symptom relief can be expected within three to four weeks of therapy but may occur sooner.⁴⁵⁸ Improvement in the vaginal maturation index (VMI) has been reported two to four weeks after the initiation of vaginal conjugated equine estrogens (Premarin) or estradiol vaginal tablets (Vagifem).⁴⁵⁹ Vaginal pH falls to its lowest levels by the third week of vaginal estrogen treatment. Superficial cells continue to increase during a 12-week course of therapy.⁴⁶⁰ Governmental regulatory bodies agree that data support the efficacy of vaginal estrogen therapy for vaginal atrophy (GSM).⁴⁶¹

Adverse events associated with use of vaginal estrogen therapy include vaginal discharge, vulvovaginal candidiasis, vaginal bleeding, and breast pain. Long-term follow-up studies on endometrial safety are not available although expert concern is low. Mild transient candidiasis is common, sometimes not requiring treatment.⁴⁶² Use of vaginal estrogen has not been found to be associated with risk of breast cancer. Vaginal estrogen treatment in women not exposed to systemic menopause hormone therapy for greater than 18 years showed the risk of cardiovascular disease, cancer, and hip fracture to be similar to that of non-users of vaginal estrogen.⁴⁶³

Choosing which form of vaginal estrogen to use must take into account patient preference, concern about estrogen exposure, and cost. Dose and length of treatment need to be individualized. For women with significant vulvar symptoms, including cracking and fissuring, initial treatment with externally applied creams in addition to internal application should be considered. The patient should be counseled that response to therapy usually takes from 4 to 6 weeks. Once symptom relief is obtained, treatment should continue indefinitely. To date, clinical studies have not extended beyond a year in follow-up, and no time limits for therapy use have been established.

Local vaginal estrogen is so effective for treatment of vaginal atrophy that “atrophy unresponsive to estrogen” should prompt re-evaluation for other sources of complaints that continue after an appropriate duration of local estrogen treatment: e.g. dermatosis such as lichen sclerosus or lichen planus, contact dermatitis, other vaginitis, especially desquamative inflammatory vaginitis, and vulvar pain of all types.

Although circulating estrogen concentrations generally remain within the menopause range with low-dose vaginal estrogen therapy, the package insert for these products includes the same black boxed warning regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and probable dementia that accompanies systemic estrogen products. Patients must be informed about the differences between low-dose vaginal and systemic estrogen therapy and be prepared for the boxed warning, or else they may not initiate prescribed treatment.⁴⁶⁴ Multiple studies have shown that topical estrogen products do not carry the same risk as oral medications.⁴⁶⁵

As mentioned above, cost is a consideration and insurances vary in their preferred products. Savings coupons for some products are available but do not work with federally funded health plans (Medicaid, Medicare). Many estrogen products now require “prior authorizations:” applications by office staff to insurance companies to explain why a particular product is needed. This work adds to costs. https://en.wikipedia.org/wiki/Prior_authorization

Vaginal estrogen creams

Vaginal creams contain conjugated equine estrogen (Premarin cream), estradiol (Estrace cream or generics), or promestriene. It is possible to compound a cream with the weaker estrogen, estriol. Although commercial estriol is available in Europe, it is not FDA approved in the USA.

Conjugated equine estrogens (CEE) (Premarin) cream 0.625 mg/gm is effective in doses of 0.5 to 2 grams (0.3 mg to 1.25 mg CEE) delivered in schedules ranging from once daily to two or three times weekly.⁴⁶⁶ The recommended initiation of therapy is 0.5 g of CEE daily into the vagina for three weeks followed by twice-weekly administration thereafter. This amount comprises one-eighth of the applicator sold with the cream and contains 0.3 mg of conjugated estrogen. Vaginal cytology in postmenopausal women given daily 0.5 g conjugated estrogen intravaginally, changed to cytology of normal premenopausal women, even though serum estrone and estradiol concentrations did not increase substantially.⁴⁶⁷ There is no similar information for estradiol vaginal cream.

Estradiol cream, obtained from soy and yams, can also be given by vaginal applicator at a dose of one-eighth of an applicator or 0.5 g (which contains 50 mcg of estradiol). The package insert indicates a maximal dose of 2.0 g daily, but this is not generally necessary. This produces premenopausal plasma levels of estradiol⁴⁶⁸ and should not be used long-term without endometrial assessment.

Many women object to the use of equine estrogen and request estradiol; some insurances, however, will not cover estradiol but do cover equine estrogens. The patient may need to inquire about her coverage prior to initiation of therapy.

Estriol is a relatively weak natural estrogen that is used outside the US to treat vulvovaginal atrophy. Brand names include Ovestin and Gynest. A low-dose estriol vaginal gel (0.005%) has been shown to signifiantly improve the vaginal maturation index (MVI) and vaginal pH compared with a baseline evaluation in postmenopausal women.⁴⁶⁹ Estriol is not approved by the FDA for any indication.

Occasionally, topical estrogen cream can burn slightly for a minute or two after application, even in women with normally estrogenized tissue. In the presence of severe VVA, the loss of the normal epithelial barrier may cause burning with any contact, even plain water in extreme cases. Estrace and Premarin cream may burn for this reason, or because they contain preservatives and alcohols that irritate. This situation can sometimes be avoided by restoring the epithelial barrier: the patient is asked to soak twice daily (to hydrate the epithelium) for five minutes in warm water, then apply a film of plain Vaseline around the introitus (to seal in the moisture and restore the epithelial barrier). After two weeks, she should try a small amount of topical estrogen as a test. If that is tolerated, she may proceed with normal application of the product. An alternative is to compound estradiol 0.1% in petrolatum or another bland base, e.g. versabase or lipoderm base. Compounding half-strength estradiol 0.05% cream is yet another option.

If the above measures are not successful, it is important to realize that the physical application of the topical treatment may be acting as a trigger to provoke pain. Encourage the woman to use gentle, light, and slow touch to expose the tissues and to apply the medication.

Estrogen creams applied topically may NOT be irritating, on the other hand, and may offer more immediate soothing relief of symptoms, possibly due to the emollient effect. Topical digital application in the vestibule directs the cream precisely and effectively, while internal use with an applicator helps improve the vaginal environment. Some women, however, consider the creams messy. (Vaginally applied creams do drip out in the form of discharge during the day after night time application). Sensitivity to the vehicle used in the creams has also been reported. With estrogen cream, the patient has the responsibility of preparing the dose because the amount of cream inserted is not in a prepackaged dosing unit. This has the potential for error, with inadvertent higher-than-recommended dosing. The potential risk for male partner estrogen absorption remains unknown.

Vaginal estrogen tablets

Vaginal estrogen tablets contain 10.3 mcg of estradiol hemihydrate which is equivalent to 10 mcg of estradiol. Vagifem was the first of this class of product to be shown effective for relief of vaginal symptoms and came out in the United States in 2010.⁴⁷⁰ The tablets are packaged in individual vaginal applicators and used nightly for 14 nights, followed by twice weekly maintenance therapy.

While the 10 mcg tablet can be useful for patients who need to minimize systemic absorption of estrogen (e.g. women with breast cancer), and is significantly more effective than placebo therapy, it appears to be slightly less effective than the original 25 mcg dose (now unavailable) for initially inducing epithelial cell maturation, providing relief of vaginal symptoms, decreasing pH, and improving urogenital atrophy.⁴⁷¹ The use of three times weekly dosing for a total of 30 mcg weekly is helpful in cases where twice-weekly Vagifem 10 mcg is not sufficient. Yuvafem is the name of a generic form of Vagifem and is used in the same way. It is usually less expensive. The typical serum estradiol level (pg/mL) is 5.5 (10ug insert).

Imvexxy is another vaginal estrogen treatment option approved for moderate to severe dyspareunia due to menopause.⁴⁷² Imvexxy is an estradiol soft gel vaginal insert that offers an applicator-free experience and any time-of-day dosing, which may help support patient compliance.⁴⁷³ The vaginal inserts are applied daily for 14 days followed by twice weekly administration. Imvexxy has the only ultra-low dose vaginal estradiol as it is available in both 4 mcg and 10 mcg doses.^{474 475 476} Typical serum estradiol level (pg/mL) is 3.6 (4 ug insert) and 4.6 (10 ug insert).

Vaginal ring

A silastic ring impregnated with estradiol (Estring, Phadia) delivers 7.5 mcg of estradiol locally to the vagina daily for a period of three months.⁴⁷⁷ At that time, the woman or clinican replaces it with a new ring. The estradiol-releasing vaginal ring with its 3 months of action does improve adherence.

The product has proven efficacy in multiple placebo-controlled RCTs,^{478 479 480} providing relief of genitourinary symptoms, including dyspareunia, dysuria, and urge incontinence. Serum estradiol levels with use of the low-dose vaginal ring remained in the postmenopausal range (from 5 pg/mL to 10 pg/mL). ⁴⁸¹ The risk of VTE was not increased in a 2020 systematic review of RCTs and three large observational studies.⁴⁸²

Patients should be encouraged to remove and replace their own rings if technically possible. The ring can remain in the vagina during sexual activity but may change position, occasionally tightly encircling the cervix, or dislodge with bowel movements, Valsalva maneuvers, douching, or vaginal sexual penetration. In some women, especially those with vaginal prolapse, retention of the ring may be difficult.

Another vaginal ring, (Femring), releases systemic levels of estradiol acetate (50 to 100 mcgs per day) and is not recommended for treatment of vulvovaginal atrophy (GSM) alone.

Vaginal estrogen absorption and need for progestogen

The question of possible need to use progestogen in conjunction with local vaginal estrogen therapy remains an area of controversy. Opinions range from a belief that progestogen is needed with any kind of vaginal estrogen to the belief that progestogen offers little, if any benefit and adds significant risk. Progestogen therapy can expose the patient to side effects including drowsiness, swelling, and breast pain (more common with DMPA/DepoProvera), acne and hirsutism (more common with norethindrone), dizziness or fatigue, or adverse mood effects.

The controversy revolves around the theoretical risk of systemic estradiol absorption. Commonly used vaginal estrogen regimens (7.5 mcg ring, 10 mcg tablets, and 0.3 mg CCE cream) were previously thought to yield minimal increases in serum estradiol concentrations (within the normal postmenopausal range).^{483 484} The estradiol assays used for these studies, however, were not sufficiently sensitive for accurate assessment of systemic absorption.⁴⁸⁵ Newer, highly sensitive assays have detected increased estradiol levels, but not to premenopausal levels.⁴⁸⁶

A recent Medline and Pubmed search showed that low dose vaginal estrogen, arbitrarily defined as the 7.5 mcg vaginal ring and the 10 mcg vaginal tablet, increases plasma estradiol levels during chronic administration, but not above the normal postmenopausal range of<20 pg/ml. Intermediate doses of 0.3 mg conjugated equine estrogen cream result in plasma estradiol levels approaching or exceeding 20 pg/ml. ⁴⁸⁷

The North American Menopause Society, in its 2020 position statement on the treatment of GSM, concluded, that based on available limited safety data, use of a progestogen^{488 489} and routine endometrial surveillance^{490 491 492} are not recommended in low-risk women using low-dose vaginal ET. Women at increased risk of endometrial cancer because of obesity or diabetes may warrant endometrial surveillance. Any patient on vaginal estrogen therapy who experiences spotting or bleeding requires a thorough evaluation that may include transvaginal ultrasound (TVU) and/or endometrial biopsy.⁴⁹³

Other experts define low dose topical estrogen as ≤0.5 g conjugated estrogen or ≤50 mcg estradiol, and state that a progestogen is probably not necessary to protect against endometrial hyperplasia in women receiving daily, local, low dose estrogen (0.3 mg conjugated estrogen) for vaginal atrophy. A progestogen should be taken when estrogen doses above these levels are used.⁴⁹⁴ No cases of atypical endometrial hyperplasia or endometrial carcinoma causally associated with the use of any local estrogen have been reported in the literature.⁴⁹⁵

Another systematic review of 20 RTCs on the use of isolated vaginal estrogen for 12-52 weeks in postmenopausal women, showed the rate of endometrial cancer and hyperplasia to be 0.03% and 0.4% respectively. Limited available studies indicate no clear endometrial proliferation although systematic endometrial biopsies were not performed.⁴⁹⁶

Still other experts suggest individualization of the decision to use progestogen during low-dose vaginal estrogen therapy.⁴⁹⁷ While measurement of endometrial thickness is widely used for monitoring during use of local estrogen, reliability and accuracy are not yet documented. Studies of the endometrial effects in women who have been treated with low dose vaginal estrogen therapy for longer than one year have not been done, but should be undertaken.

ACOG and NAMS advise that low-dose vaginal estrogen can be used indefinitely and do not advise discontinuation at a specifc age.^{498 499}

Estrogen replacement therapy and Candida

Estrogen provides a high glycogen content in the vaginal environment, yielding an excellent carbon source for Candida growth and germination. Estrogen also enhances the ability of the vaginal epithelial cell to adhere to Candida, leading to invasion of the cell and infection. A receptor or binding system for female reproductive hormones has been documented in Candida cells.⁵⁰⁰

It is uncommon for postmenopausal women not on hormone therapy to experience yeast infection. In contrast, it is possible for a woman to be yeast-free until the commencement of hormone replacement therapy at menopause. In the postmenopausal woman, it is essential to document Candida by microscopy and culture since the differential diagnosis of itching, burning, and erythema includes atrophy, dermatosis, and vulvodynia. Recurrent yeast (more than three documented positive cultures in a year) may require adjustment of estrogen use to a lower level, discontinuation of estrogen therapy, or suppression with fluconazole 150 mg weekly.

Table P-24: Local treatment of vaginal atrophy with estrogen, lowest to highest doses⁵⁰¹

Selective estrogen receptor modulators

Selective estrogen receptor modifiers (SERMS) use their varied effects on alpha and beta estrogen receptors to produce unique therapeutic effects. Ospemifene, a SERM, is an oral agent appproved for the treatment of women with moderate to severe dyspareunia associated with VVA.⁵⁰² Daily use of the 60 mg pill improves the vaginal maturation index, vaginal pH, and symptoms of GSM.⁵⁰³ The most common side effects of ospemifene are hot flashes and urinary tract infections.⁵⁰⁴ Ospemifene treatment can be associated with significantly greater endometrial thickness after one year of use.⁵⁰⁵

Ospemifene labeling states that the drug should not be used in women with known or suspected breast cancer because it has not been adequately studied in this group. However, its use has been associated with a decreased risk for breast cancer and breast cancer recurrence in preliminary studies.⁵⁰⁶ Clinical studies indicate that ospemifene improves bone markers significantly more than placebo and comparable to oral estrogens and other SERMs approved for osteoporosis treatment and prevention. In women with vaginal dryness and low bone density, ospemifene may offer an advantage over locally applied estrogens.⁵⁰⁷ Ospemifene may also be a superior choice in patients who cannot tolerate local medications (such as patients with Bechet’s). Patient preference is also a consideration.

Not all SERMs have the same clinical effects on GSM. Tamoxifen and raloxifene do not improve vaginal symptoms. Duavee (bazedoxifene in combination with oral conjugated equine estrogens) does improve symptoms of vaginal atrophy but the improvement in symptoms may be related to the equine estrogens alone.

Vaginal androgen therapy

Androgens contribute to the maintenance of genitourinary tissue structure and function. The effects of androgens can be distinct from those of estrogens or can be complementary. Recent research has shown that androgen-mediated processes may be involved in the full or partial resolution of GSM in women.⁵⁰⁸

Vaginal prasterone

A daily intravaginal insert of DHEA/prasterone was approved in 2016 for the treatment of dyspareunia secondary to moderate to severe vulvovaginal atrophy. DHEA is an endogenous steroid, converted by aromatase activity at the intracellular level into androgens and estrogens. The suppository is designed to be placed in the vagina nightly.

Compared to placebo, vaginal prasterone for 12 weeks was associated with improvement in dyspareunia, pH, and vaginal maturation and there were no endometrial changes.⁵⁰⁹ Circulating steroid levels remained within the normal range for postmenopausal women.⁵¹⁰⁵¹¹

A retrospective cohort analysis showed women treated with prasterone had a significantly lower incidence of UTI compared to those with untreated GSM.⁵¹² Recent expert opinion suggested that intravaginal DHEA may be effective in the treatment of other types of sexual dysfunctions, such as decreased lubrication, decreased sexual desire, and decreased sexual satisfaction. Further studies, which consider alternative dosing and indications, are pending.⁵¹³

Breast cancer risk has not been fully evaluated for vaginal DHEA, although the FDA-approved labeling for this intervention lists breast cancer as a warning, without a contraindication.

Vaginal testosterone

Intravaginal testosterone has been studied in short-term interventions (4-12 weeks). Fernandes et al randomized women aged 40-70 to receive one of these vaginal treatments: conjugated estrogens, testosterone proprionate, or placebo (glycerin lubricant) applied three times a week for 12 weeks. Both testosterone and estrogen treatments reduced the pH to <5 and increased the vaginal cell score and the number of lactobacilli. Analyses of serum hormone levels at 6 and 12 weeks showed no significant differences between treatment and placebo groups with no changes in endometrial thickness observed in any of the groups.⁵¹⁴ A meta-analysis concluded that the effect of vaginal testosterone on sexual function and sexuality scores were similar to that of estrogen therapy.

In breast cancer survivors taking aromatase inhibitors, sexual interest, sexual dysfunction, and satisfaction had more improvement in the group receiving testosterone compared to the group receiving estrogens.⁵¹⁵ However, dyspareunia or vaginal dyness were not assessed. Longer and larger studies are needed to assess the safety and efficacy of this therapy.⁵¹⁶

Lidocaine

Another nonhormonal option for women with severe penetrative dyspareunia is the use of topical lidocaine. Over the counter, as well as prescription preparations, are available at varying strengths. In one study, 4% aqueous lidocaine applied to the vulvar vestibule before vaginal penetration resulted in significant improvements in dyspareunia and sexual function.⁵¹⁷

Patients should be instructed to fully saturate a cotton ball (or more than one depending on size) or a cotton swab with 4% or 5% aqueous lidocaine and then hold the cotton ball or swab against the vulvar vestibule for three minutes before vaginal penetration takes place.⁵¹⁸

Direct applicaton of lidocaine may result in discomfort (burning), so lower strengths and dilution in a water-based lubricant may be recommended initially. Lidocaine may affect the partner’s sensation. Allergic-like reactions have been reported but are rare.

Pelvic floor rehabilitation and vaginal dilators

Pelvic floor physical therapy is well established in the treatment of urinary incontinence and may be used as an adjuvant treatment for urinary symptoms of menopause. More recently, pelvic floor muscle training has been shown in studies to significantly reduce symptoms of vulvovaginal atrophy in postmenopausal women, as well. Mercier, et al demonstrated that a 12 week program by physical therapists increases vaginal wall lubrication, thickens the vaginal epithelial surface, and improves vaginal color. The decrease in VVA signs and urinary symptoms is therorized to be related to improved blood flow in the arteries supplying vulvovaginal tissues, improved pelvic floor muscle relaxation capacity, and increased vulvovaginal tissue elasticity.⁵¹⁹ Starting pharmacologic tratment ot restore tissue integrity before initiating pelvic floor physical therapy may facilitate progress.

Vaginal dilators of graduated sizes can play an important role in restoring and maintaining vaginal function for penetration. Vaginal dilators primarily provide the fearful woman, traumatized by atrophy-related dyspareunia, with a way to trial treatment effects by, in the privacy of her home, inserting graduated dilators to test for pain and gain in confidence that treatment is working. Dilators may restore vaginal capacity by expanding the vagina in width and depth allowing for comfortable sexual activity. They are also useful for vaginal stenosis, vaginismus (pelvic floor myalgia), and after pelvic radiation therapy. See Annotation L for more on the use of dilators.Annotation L: click on Vaginal Dilators

This article from Sloan Kettering provides helpful instructions for patients in how to use dilators:

https://www.mskcc.org/cancer-care/patient-education/how-use-vaginal-dilator

Diltors may be washed with warm water and mild soap. Silicone dilators may be sterilized by boiling for 5 minutes or by autoclave. GRS (gender reassignment surgery) and Rigid Plastic dilators can NEVER be boiled or autoclaved. Lubricant use with dilators may have some restrictions (e.g., silicone lubricants should not be used with silicone dilators). There are many types of dilators available. The authors use Soul Source dilators manufactured in the United States or those available at Vaginismus.com https://www.vaginismus.com/ where they are called “inserters.”

Energy-based therapies

The US Food and Drug Administration (FDA) has licensed the CO2 laser systems for “incision, excision, ablation, vaporization, and coagulation of soft tissues in the body.” These devices have been used in specialties such as dermatology, ENT, urology, neurosurgery, and gynecology since 2010. FDA authorized indications for energy-based devices for gynecology include the destruction of abnormal cervical or vaginal tissue, condyloma, and precancerous lesions. Since then, many health professionals, physicians, and nonphysicians have adopted using such energy-based devices without a precise indication, including the promise of genital “rejuvenation.”

Vulvovaginal energy-based devices, including lasers (fractional CO2, Erbium: YAG and radio-frequency devices) are under investigation as treatments for GSM, but none have FDA approval for this indication. In a 2018 Safety Communication, the FDA issued a public warning about the use of these devices for vaginal cosmetic purposes, stating that the effectiveness and safety of the devices have not yet been established.⁵²⁰

The main benefits of energy-based device use in the vagina are purported to be as follows: a) thickening of the non-keratinized epithelium, b) increase in local angiogenesis, c) improvement in lubrication, d) normalization of the genital microbiome, e) decline in vaginal pH, f) development of new collagen fibers and restoration of vaginal architecture, improvement in elasticity and decrease in the frequency of microtraumas, and g) improvement in genitourinary symptoms.⁵²¹

Adverse events associated with energy-based therapies include discomfort during treatments, vaginal scarring, vaginal lacerations on resumption of intercourse, and persistent and/or worsening dyspareunia.⁵²² The recommended course of therapy includes three treatments which are costly and generally not covered by insurers. The effect of the treatment seems to be transitory for most women and repeat courses of treatment are often necessary.

Consensus statements regarding the use of energy-based therapies for GSM treatment have been published by several professional societies summarizing the small but growing body of evidence, and expressing concerns about safety.^{523 524 525} Currently, the International Society for the Study of Vulvovaginal Disease (ISSVD) does not endorse the use of these technologies out of the setting of clinical trials.⁵²⁶ The American College of Obstetricians and Gynecologists’ (ACOG) 2021 Clinical Consensus No.2 on the treatment of urogenital symptoms in women with estrogen-dependent breast cancer states: “Laser therapy has shown promise in a research setting, with small trials.”⁵²⁷

Data from a recent meta-analysis suggests that CO2 laser is a safe energy-based therapeutic option for the management of VVA and/or GSM symptoms in postmenopausal women; however, the quality of the body of evidence found was “very low” or “low.”⁵²⁸ Until well-designed RCTs versus placebo or other interventions are available, these procedures should be cautiously used for the treatment of GSM.

In the absence of adequate clinical trials, patients who desire these treatments should be referred to a practitioner with extensive experience performing the procedure. If energy-based technology is offered to the patient as a treatment option, the indication for the procedure should be conveyed in a clear and transparent way. An explanation on the limitations and risks of the method should also be proviced.

Treatment of women with breast cancer

Many patients and clinicans remain hesitant to use any estrogen-related compounds in this patient population. In addition, adjuvant treatments (aromatase inhibitors (AIs) or tamoxifen) work by either lowering estrogen concentrations or antagonizing estrogen effects. For pre-and post-meopausal patients receiving these treatments, the vulvovaginal symptoms that result from the effect of estrogen loss may be negatively life-altering. Fortunately, most new data do not show an increased risk of cancer recurrence with vaginal estrogen use among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer. However, in a study of postmenopausal patients with a history of early estrogen-positive breast cancer treated with aromatase inhibitors (AI), those who used vaginal estrogen after the breast cancer diagnosis had a higher risk of breast cancer recurrence compared with nonusers (adjusted hazard ratio 1.39, 95% CI 1.04-1.85), an effect not seen in patients treated with tamoxifen. The authors of the current UpToDate article on Treatment of VVA, therefore, only prescribe vaginal estrogen for GSM to their patients being treated with tamoxifen, not AI. ⁵²⁹

Breast cancer patients with GSM may benefit from nonhormonal therapies including lubricants, moisturizers, and pelvic floor physical therapy. If symptoms persist, however, other therapies may offer relief and should be offered, including topical lidocaine, low-dose vaginal ET, vaginal DHEA, ospemifene, and possibly vaginal energy-based therapies.^{530 531 532 533}

According to FDA labeling, even low-dose ET is contraindicated in women with breast cancer. Off-label use of several products can be employed because of their very low systemic absorption.⁵³⁴ Low dose vaginal ET formulations, including the estradiol tablet, insert, and ring, result in serum estradiol within the postmenopausal range and similar to placebo blood levels.^{535 536} Several organizations, including the American College of Obstetricians and Gynecologists and the North American Menopause Society, have endorsed the use of low-dose vaginal estrogens in women with breast cancer, including ER-positive disease. Based on a recent meta-analysis,⁵³⁷ the International Society for the Study of Vulvovaginal Disease (ISSVD) concluded that vaginal estrogen use was not associated with significant absorption, which provides indirect evidence of safety.⁵³⁸

Use of vaginal DHEA for GSM in women with breast cancer is not contraindicated according to the FDA, but US labeling advises caution because estrogen is a metabolite of DHEA.⁵³⁹ Although vaginal DHEA has not been studied in women with a history of breast cancer, levels of estradiol and testosterone remain within the postmenopausal range in non-breast cancer afflicted women.⁵⁴⁰

Ospemifene is not recommended for treatment of GSM in women with known or suspected breast cancer because the drug has not been adeuately studied in this group.

Clinical trials of energy-based therapy (laser) for GSM in survivors of breast cancer provide limited evidence for safety and efficacy in this patient population.

In all women with a history of or high risk for breast cancer, but especially those on AI, estrogen preparations with the lowest absorption such as the 4 mcg capsule or the 10 mcg tablet or capsule are a reasonable choice. The fact remains that a safe level of serum estrogen in relation to breast cancer risk is not known for women on or off adjuvant hormonal treatment, while quality of life concerns are important to these women. Shared decision making and involvement of the patient’s oncologist are important.

In breast cancer survivors with dyspareunia and not using vaginal estrogen, exquisite pain can sometimes be elicited with simple touch of the vulvar vestibule. This pain may be attenuated with pre-coital application of aqueous lidocaine 4%. Vaginal tenderness was rare despite severe atrophy.⁵⁴¹

The American College of Obstetricians and Gynecologists (ACOG) has made the following recommendations:⁵⁴²

• Nonhormonal approaches are the first-line choices for managing urogenital symptoms or atrophy-related urinary symptoms experienced by women during or after treatment for breast cancer.
• Among women with a history of estrogen-dependent breast cancer who are experiencing urogenital symptoms, vaginal estrogen should be reserved for those patients who are unresponsive to nonhormonal remedies.
• The decision to use vaginal estrogen may be made in coordination with a woman’s oncologist. Additionally, it should produced by an informed decision-making and consent process in which the woman has the information and resources to consider the benefits and potential risks of low dose esterogen.
• Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms.

Estradiol can be compounded in any desired strength.

Natural and bio-identical hormones

Women assume that “natural” hormones–any products whose principal ingredient has an animal, plant, or mineral source–would be better or safer. The term “natural” is confusing, sometimes referring to source of preparation from a plant or animal, sometimes referring to chemical structure identical to human.(Premarin is natural estrogen, but it comes from horse urine and is horse estrogen). ⁵⁴³ The only true natural estrogens are those manufactured in the human female body: estrone, estriol, and estradiol. These are not available commercially. In addition, “natural” does not necessarily guarantee safety since many natural products are unregulated.

“Bioidentical” is a term referring to products that contain hormones chemically identical to those found in humans. The interest in a more natural approach to hormone therapy has focused attention on bioidentical hormones. These are not found in nature but are made, or synthesized, from a plant chemical extracted from yams and soy.⁵⁴⁴ A hormone is bioidentical when it has the exact structure of estrone, estriol, or estradiol, whether it comes from the ovary or is extracted from plants. Multiple specially compounded formulae have no advantage over commercially manufactured, FDA approved estradiol except if special dosage is required or when a special vehicle is needed in the case of particularly sensitive women.