NAMS Position Statement: The 2020 Genitourinary Syndrome of Menopause Position Statement of the North American Menopause Society

Menopause. 2020;27(9):976-992. 

In This Article

Treatment

The primary goal of treating GSM is to alleviate symptoms. For the woman with GSM, after excluding other causes of her symptoms, treatment can be approached in a stepwise fashion based on symptom severity. First-line therapies for less-severe symptoms include nonhormone vulvar and vaginal lubricants with sexual activity and long-acting vaginal moisturizers used regularly (several times/wk). Although not supported by clinical trials, regular, gentle vaginal stretching exercises (eg, pain-free insertion of a finger or dilator) or sexual activity may reduce GSM symptoms. Prescription therapies include low-dose vaginal estrogens, vaginal DHEA inserts, and oral ospemifene. For women with moderate to severe dyspareunia associated with GSM with concurrent VMS, transdermal and oral HT are effective options. Symptom reduction may take 1 to 3 months, and continued therapy is generally required because symptoms are likely to recur on cessation of treatment. Outcomes data on the symptom recurrence rate are lacking.

Some women may already have vaginal narrowing or provoked pelvic floor hypertonia limiting vaginal penetration. Gentle stretching of the vagina with the use of lubricated vaginal dilators of graduated sizes (or an expandable dilator) can play an important role in restoring and maintaining vaginal function for penetration. Reinitiating regular sexual activity once vaginal penetration is again comfortable, if desired, may help to maintain vaginal pliability. Many women with this condition benefit from referral for pelvic floor physical therapy (PFPT).[69,70] Starting pharmacologic treatment to restore tissue integrity before initiating vaginal dilatation and/or PFPT may facilitate progress.

Nonprescription Therapies

Lubricants and Moisturizers. First-line therapies to alleviate symptoms of GSM include over-the-counter (OTC) nonhormone vaginal lubricants and moisturizers, a number of which are available (Table 1), but few clinical studies have been conducted on the efficacy of these products.

A vaginal moisturizer is a bioadhesive product used regularly, most often two to three times a week, irrespective of the timing of sexual activity. The goal of use is to reduce daily symptoms of GSM as well as to facilitate comfortable sexual activity. Data suggesting improvement in genitourinary symptoms with nonhormone treatments are sparse, and to date, there are no adequately powered, randomized, double-blind, placebo controlled studies directly comparing low-dose vaginal estrogen therapies or vaginal DHEA with commonly used nonhormone treatments. One randomized, controlled, but short-term study demonstrated effectiveness of a pH-balanced gel compared with placebo in women treated for breast cancer. Mild irritation with administration was noted.[71] In a randomized, controlled trial (RCT; N = 302), a significant improvement in most bothersome symptom severity was seen in all three arms: the vaginal estradiol tablet (plus placebo gel), vaginal moisturizer (plus placebo tablet), and dual placebo arms.[72] In that trial, the placebo gel likely had lubricating properties.

Vaginal lubricants are used by both (or all) partners to decrease discomfort caused by friction during sex. Regular use has also been associated with increase in pleasure and ease of orgasm.[73] In a review and meta-analysis, the effect of lubricant use on symptom severity could not be compared in studies because of heterogeneity. However, the meta-analysis of sexual function outcomes showed a small advantage to hormone-based therapies over lubricants in restoring sexual function.[74] One small crossover study in survivors of breast cancer demonstrated greater benefit with silicone-based lubricants compared with water based.[75]

In studies examining the safety of personal moisturizers and lubricants, investigators found that a number of water-based products are hyperosmolar.[76,77] This characteristic is associated with epithelial cellular toxicity and damage in cultures of epithelial cells and ectocervical explants. Near iso-osmolar and silicone-based lubricants did not have this effect. The World Health Organization recommends an osmolarity of less than 1,200 mOsm/kg.[78] One jelly and one moisturizer also were found to be toxic to lactobacilli. There are very few data on the health and safety effects of lubricants that contain flavors (sugar), warming properties, or solvents and preservatives such as propylene glycol and parabens. One study on the use of vaginal products in women aged 18 to 65 years reported a 2.2-fold risk of BV in women using petroleum jelly compared with controls and increased colonization with candida species with users of oils compared with nonusers.[79]

Because there are no published reports on the irritation potential of OTC vaginal lubricants and moisturizers, women can test these 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 (Table 1). 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.

Hyaluronic Acid. Hyaluronic acid is a polymer found in cartilage and other soft tissues in the body that is added to many commercial skin-care and wound-healing products because of its purported effect of drawing moisture to any area to which it is applied. In four small RCTs comparing hyaluronic acid to placebo or vaginal ET, the former was associated with a similar decrease in severity of dryness and dyspareunia.[80–83] To date, there is no evidence that products with hyaluronic acid have a greater benefit than nonhyaluronic acid lubricants or moisturizers.

Herbal Products. Herbal products appear ineffective for GSM. The Herbal Alternatives for Menopause study, a double-blind RCT in 351 women, identified no change in vaginal dryness, vaginal cytology, follicle-stimulating hormone or estradiol levels following treatment for 1 year with black cohosh, a multibotanical supplement, or soy.[84]

Prescription Therapies

For women with persistent GSM symptoms after nonhormone interventions, prescription therapies may provide greater benefit.

Vaginal Estrogen. Estrogen delivered vaginally provides sufficient estrogen to relieve genitourinary symptoms with minimal absorption and is preferred over systemic therapy when only genitourinary symptoms are present.[85,86] When systemic HT is needed to treat other menopause symptoms, a woman also will generally derive satisfactory resolution of her genitourinary symptoms, although additional low-dose vaginal estrogen may be added if needed.

Efficacy studies of low-dose vaginal ET use both subjective and objective outcome measures. Subjective effects are often assessed using patient-reported outcome measures that include improvements in symptoms such as dyspareunia, vaginal dryness, and lower urinary tract symptoms and clinician-reported outcomes such as the appearance of the vulvovaginal tissues. Objective outcomes include decreases in vaginal pH, increases in the number of vaginal lactobacilli, and favorable shifts in the vaginal and/or urethral cytology (greater numbers and percentages of superficial cells and fewer numbers and percentages of parabasal cells).[87,88]

Efficacy. Low-dose vaginal ET is available in several forms, including cream (estradiol, estrone, and conjugated estrogens), a slow-release estradiol intravaginal ring, and an estradiol vaginal tablet and insert. Products vary in dosage and formulation (Table 2).[89–97] All approved products have proven efficacy in placebo-controlled RCTs.[86,98–111] In the United States, FDA requires efficacy data for treatment of a specific, most bothersome symptom, which includes dyspareunia, vaginal dryness, vaginal/vulvar irritation, vaginal soreness, dysuria, or bleeding associated with sexual activity. Dyspareunia and vaginal dryness are the most common indications for low-dose vaginal ET.

The comparative efficacy of the various forms of vaginal ET was evaluated in a 2016 Cochrane review comparing 19 trials.[112] This review concluded that all tested products alleviated symptoms of vaginal dryness and dyspareunia with similar efficacy. Comparative analyses of these trials are limited by variations in methods and outcome measures, small sample sizes, lack of blinding, and substantial heterogeneity of results. Some trials of the same estrogen preparation used different doses or dosing schedules. Some trials included preparations not approved for use in the United States or in Canada.

Vaginal Estrogen and Urinary Symptoms. In a 2014 systematic review that included 44 RCTs, assessment of urinary symptoms was variable, leading to a lower quality of evidence for the effectiveness of vaginal estrogen for urinary symptoms compared with vulvovaginal symptoms.[113] This review reported moderate-quality evidence supporting vaginal ET in the treatment of urge incontinence and recurrent UTIs and low or very-low quality evidence supporting the use of vaginal ET for improvement of dysuria, urinary frequency and urgency, nocturia, and stress incontinence.

A Cochrane review of vaginal ET for urinary incontinence determined that vaginal ET improves incontinence (relative risk [RR], 0.74; 95% confidence interval [CI], 0.64–0.86) but that systemic estrogen alone and in combination with a progestogen worsens incontinence (RR, 1.32; 95% CI, 1.17–1.48 and RR, 1.11; 95% CI, 1.04–1.18, respectively).[114] Most of these studies were conducted for reasons other than urinary symptoms, failed to use validated tools to assess symptom severity and QOL, and showed statistically significant but not clinically relevant changes. For example, in the Heart and Estrogen/Progestin Replacement Study, women randomized to systemic oral estrogen plus progestogen therapy experienced 0.7 more leak episodes per week compared with 0.1 fewer episodes in the placebo group, but both changes met the a priori definition of "no change in incontinence severity."[115]

Few trials have been conducted comparing vaginal ET to other treatments for postmenopausal urinary tract symptoms. Two small trials comparing vaginal ET (conjugated equine estrogens) to pelvic floor muscle therapy (PFMT) for urinary incontinence favored PFMT over vaginal estrogen,[114] but a trial that compared estriol alone to estriol combined with pelvic floor rehabilitation favored combined therapy.[69] A comparison of the estradiol ring to oral oxybutynin showed similar efficacy for treatment of overactive bladder but with different AEs; oxybutynin resulted in more dry mouth, constipation, and blurry vision, whereas the estradiol ring resulted in more vaginal discharge.[116] When women present with both vulvovaginal and urinary symptoms, an initial trial of vaginal ET is prudent. If urinary symptoms are not sufficiently improved or resolved after 3 months of vaginal ET, the use of other evidence-based therapies for urinary tract symptoms is warranted.[117]

Recurrent UTI, defined as the occurrence of two culture-proven UTIs in 6 months or three culture-proven UTIs in 1 year, commonly affects postmenopausal women and is a component of GSM.[118] Treatment of GSM with vaginal ET (conjugated equine estrogen cream or low-dose estradiol vaginal ring) in a small RCT reduced the frequency of recurrent UTIs in postmenopausal women.[119] An RCT of vaginal estriol cream (0.5 mg) in postmenopausal women with recurrent UTIs led to a significant decrease in number of UTI episodes per year (0.5 compared with 5.9).[120] In another randomized trial, the low-dose estradiol ring was found to prolong the time to next recurrence in postmenopausal women with recurrent UTIs and to decrease the number of recurrences per year (RR, 0.64).[121]

Women who use a vaginal pessary for treatment of uterovaginal prolapse are often advised to use vaginal ET to facilitate pessary use and to limit potential complications such as vaginal discharge and vaginal wall erosions. Prospective data are lacking, but observational studies show lower discontinuation rates and less vaginal discharge when pessary users are treated with vaginal ET.[122]

Safety. Low-dose vaginal ET has a more favorable risk profile than systemic ET because estrogen doses are significantly lower (Table 2).[89–97] Estrogens are systemically absorbed from the vagina in a dose-dependent manner, and in general, serum estrogen levels reported with use of low-dose vaginal ET remain within the postmenopause range.[123] A review of systemic estradiol measurements reported baseline levels in normal, untreated postmenopausal women of 3.1 pg/mL to 4.9 pg/mL using highly sensitive assays such as liquid or gas chromatography/mass spectroscopy and levels that were undetectable to 10.5 pg/mL using the less-sensitive radioimmunoassay.[85] Serum estradiol levels with use of the low-dose vaginal ring (releasing approximately 7.5 μg/d) ranged from 5 pg/mL to 10 pg/mL.[107,124,125] Serum estradiol levels with use of the 10-μg vaginal tablet ranged from 3 pg/mL to 11 pg/mL.[126–128] Serum estradiol levels after daily use of the 4-μg and 10-μg vaginal insert for 14 days were 3.6 pg/mL and 4.6 pg/mL, respectively, which was not statistically different from placebo (4.3 pg/mL). After twice weekly use for 84 days, there was no difference in serum estradiol levels compared with baseline or placebo.

Serum estradiol levels associated with use of vaginal estradiol cream are derived from older data using higher doses and less-sensitive assays that lack accuracy for lower estrogen levels.[129] Use of estradiol cream 0.5 mg (500 μg) daily for 3 weeks resulted in no change in serum estradiol levels.[130] In contrast, another study showed that daily use of estradiol cream 0.2 mg (200 μg) daily resulted in serum estradiol levels that rose from a baseline of 16.6 pg/mL to 37.2 pg/mL after 3 weeks of use.[131] Use of 0.3 mg conjugated estrogens (CE) cream 3 times weekly for 6 months produced no change in serum estradiol or estrone levels.[132] Of note, CE contains a significant number of compounds, some estrogenic and some antiestrogenic, so serum estradiol and estrone levels after use of CE may not reflect actual estrogenic activity. Vaginal bleeding, breast pain, and nausea have been reported in some trials of vaginal estrogen cream. These symptoms are dose related and suggest that the dose was large enough to result in significant systemic absorption.

Adverse events associated with use of vaginal ET include vaginal discharge, vulvovaginal candidiasis, vaginal bleeding, and breast pain. Differing AE profiles may reflect variations in product formulation and dose.[133,134]

The risks typically associated with systemic ET, including breast and endometrial cancer and cardiovascular disease (CVD), have been evaluated in several trials of vaginal ET. Clinical trial data beyond 1 year are lacking, however, because the longest duration of any RCT was 52 weeks.[135] Endometrial safety was assessed in two systematic reviews that included RCTs and large observational studies.[136,137] In 20 RCTs, 2,983 women were exposed to vaginal ET for up to 1 year. There was one case of endometrial cancer (0.03%) and 12 cases of endometrial hyperplasia (0.4%). The cases were sporadic and their incidence similar to the baseline rate in the general population. A 2016 Cochrane review of RCTs reported no significant differences among vaginal estrogen formulations in terms of endometrial thickness or hyperplasia or the proportion of women with AEs.[112] Large observational studies evaluating longer exposures to vaginal ET identified no increase in endometrial cancer. In the Women's Health Initiative-Observational Study, the rate of endometrial cancer was not statistically different in users of vaginal ET compared with nonusers (1.3 vs 1 case per 1,000 woman-years, respectively). Thus, occurrence of endometrial cancer and hyperplasia with low-dose vaginal ET use is rare and consistent with rates in the general population.

The risk of venous thromboembolism (VTE) was not increased with vaginal ET use in a 2016 Cochrane review, a 2020 systematic review of RCTs, and three large observational studies.[112,135,137–139] Of note, systematic, prospective data for women at high risk of VTE are lacking.

A prospective cohort study of approximately 45,000 women in the Women's Health Initiative Observational Study examined risks associated with vaginal ET use. Outcomes assessed included coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, and death. The findings were very reassuring, with no increased risk of CVD or cancer in postmenopausal women using vaginal estrogens.[135] Another prospective cohort study of approximately 54,000 postmenopausal women in the Nurses' Health Study also was very reassuring regarding the safety of vaginal ET. There was no increase in health outcomes assessed with vaginal ET use, including CVD (total myocardial infarction, stroke, pulmonary embolism/VTE), hip fracture, and cancer (total invasive, breast, endometrial, ovarian, and colorectal).[138] In a 2019 meta-analysis, investigators used individual participant data from 58 observational studies reported between 1992 and 2018 to assess associations between hormone therapy and breast cancer.[140] Use of vaginal estrogen was not found to be associated with risk of breast cancer.

Potential Contraindications to Vaginal Estrogen Therapy. Although most women with GSM are candidates for low-dose vaginal ET, use is contraindicated in women with undiagnosed vaginal/uterine bleeding and should be used with caution in women with estrogen-dependent neoplasia. Management of GSM in women with nonhormone-dependent cancers is similar to that for women without a cancer history. Low-dose vaginal ET has not been studied in women at increased risk of thrombosis, but may be used with caution given minimal systemic absorption, the absence of a hepatic first-pass effect, and minimal, if any, effect on prothrombotic factors. Of note, in large observational studies, neither vaginal estrogen nor systemic transdermal formulations of ET have been associated with an increased risk of VTE.[139]

Although circulating estrogen concentrations generally remain within the menopause range with low-dose vaginal ET, the package insert for these products includes the same boxed warning regarding risk of endometrial cancer, breast cancer, cardiovascular disorders, and probable dementia that accompanies systemic HT products. Women must be educated about the differences between low-dose vaginal and systemic ET and be prepared for the boxed warning, or else they may not initiate prescribed treatment.

Vaginal Estrogen Products

Several low-dose vaginal estrogen products have been government approved for use in the United States and Canada, including cream (estradiol, estrone, and conjugated estrogens), a slow-release estradiol intravaginal ring, and an estradiol vaginal tablet and insert (Table 2).[89–97] Vaginal estrogen creams are generally used two to three times weekly, estradiol tablets and inserts used twice weekly, and the estradiol ring changed every 3 months. Estrogen creams, tablets and inserts are used daily for 2 weeks at the initiation of treatment for more rapid improvement in symptoms (Table 2).[89–97] One vaginal ET product (Femring) delivers a systemic dose of estradiol and is approved for the treatment of VMS in addition to GSM.[141] Femring should not be confused with Estring, which delivers a low dose of estradiol and is indicated only for GSM. There are no data to suggest an advantage for initial use of combined systemic and vaginal estrogen in cases of severe GSM.

Therapy with low-dose vaginal estrogen can be individualized to identify the lowest dose and frequency of use that provides the desired effect. Although efficacy is similar among the available products, estrogen creams dispensed with an applicator may offer more immediate soothing relief of symptoms, possibly because of the emollient nature of the carrier. Another potential advantage of the creams is that they can be digitally applied directly to the vulvar and vestibular tissues. However, some women consider the creams messy, and some report sensitivity to the vehicle used in the creams. With estrogen cream delivery, the user has the responsibility of preparing the dose because the amount of cream inserted is not in a prepackaged dosing unit—potentially leading to use of higher-than-recommended doses. The clinical implications of potential male partner estrogen absorption remain unknown.

Low-dose estradiol tablets and inserts are convenient, fixed-dose vaginal estrogen formulations. Although two doses of the vaginal tablet (25 μg and 10 μg) were shown to be effective, only the lower dose (10 μg) is available in the United States and Canada.[101,102,107–109,111,142] There are two approved doses of the vaginal insert (4 μg and 10 μg), with the 4-μg dose providing the lowest available formulation of vaginal ET.[143–145]

The sustained-release, low-dose estradiol vaginal ring provides 90 days of continuous estradiol. Effective relief of genitourinary symptoms, including dyspareunia, dysuria, and urge incontinence, has been consistently documented in RCTs with this estrogen delivery system.[99,100,103–107] The estradiol ring may change position or dislodge with bowel movements, Valsalva maneuvers, douching, or vaginal sexual penetration, particularly in women with uterovaginal prolapse or hysterectomy. Vaginal ring users are encouraged to remove and replace their own vaginal rings unless discomfort or limited dexterity makes such self-care difficult. The ring can remain in the vagina during sexual activity. There are no data to suggest an allergic reaction to the silicone product. If there is significant stenosis of the vagina, regular use of graduated vaginal dilators after initiation of estrogen cream, tablet, or insert may be necessary before an estrogen ring can be inserted.

Given similar efficacy among vaginal estrogen formulations, women should be provided with information on all options, with personal preference guiding choice. Although some women prefer estrogen creams to allow for vulvar and vestibular as well as vaginal application, others find creams messy and dislike cleaning the applicator after use. Because creams do not provide a specific, fixed dose of estrogen, other options may be preferred if careful dosing and predictable results of serum estrogen levels are desired. Vaginal estradiol tablets and inserts are convenient, requiring only twice weekly application after 2 weeks of daily use. The tablet is placed in the vagina with a plastic applicator, whereas the insert is placed with a finger. Preference for insertion method may determine product choice. For women who are comfortable using a vaginal ring, this formulation is convenient, requiring placing a new ring only four times yearly. Vaginal estrogen formulations are often costly, and variation in price, depending on a woman's particular insurance coverage, also may be a factor in product choice.

Vaginal Dehydroepiandrosterone

Dehydroepiandrosterone (also known as prasterone) is a steroid hormone that is an intermediate in the biosynthesis of androgens and estrogens. A low-dose DHEA vaginal insert used daily with an applicator is approved in the United States and Canada for the treatment of moderate to severe dyspareunia in menopausal women (Table 2).[89–97] Dehydroepiandrosterone is transformed by vaginal mucosal cells to estrogens, including estradiol, and to androgens, including testosterone.[146] Twelve-week RCTs have demonstrated the efficacy of DHEA 6.5 mg daily in improving the VMI, vaginal pH, dyspareunia, and vaginal dryness in menopausal women with GSM. Vaginal discharge was the most common AE, reported by 6% of study participants. In 422 women receiving DHEA for 52 weeks, endometrial sampling demonstrated inactive or atrophic endometrium in all participants.[147]

Ospemifene

Ospemifene is an estrogen agonist/antagonist and the only orally available product approved for treatment of vaginal dryness and moderate to severe dyspareunia. It is available in the United States, but not in Canada.[97,148] Twelve-week RCTs have demonstrated the efficacy of ospemifene 60 mg daily in improving VMI, vaginal pH, dyspareunia, vaginal dryness, and genital exam findings.[149–151] A 52-week efficacy and safety extension study in 180 women showed sustained improvements on visual examination of the vagina, with no cases of VTE, endometrial hyperplasia, or cancer.[152] Vasomotor symptoms were the most common AE, with rates of 2% in the placebo group and 7.2% in the group taking 60 mg of ospemifene. Ospemifene was shown to reduce recurrent UTIs in a 6-month retrospective observational study.[153]

The prescribing information for ospemifene contains precautions similar to those for estrogens and other estrogen agonist/antagonists, including an increased risk of endometrial cancer and CVD.[97] With regard to breast cancer, labeling states that ospemifene should not be used in women with known or suspected breast cancer because the drug has not been adequately studied in this group. Ospemifene has, however, demonstrated antiestrogenic activity in preclinical models of breast cancer.[154] In ex vivo human breast tissue, ospemifene inhibited proliferation and opposed stimulation caused by estradiol similar to but not as potently as the estrogen agonist/antagonists tamoxifen and raloxifene.[155] Ospemifene 60 mg has been associated with decreased risk for breast cancer and breast cancer recurrence in preliminary studies.[156]

Duration of Therapy and Monitoring

Improvement in GSM symptoms typically occurs within a few weeks of starting therapy;[157] however, treatment for 12 weeks may be needed for maximum benefit. In the absence of contraindications, therapy should be continued as long as needed for symptom management as symptoms will recur upon discontinuation. Clinical trial safety data are limited to 1 year, but observational studies demonstrate safety with long-term use.

Based on available limited safety data, use of a progestogen[112,126] and routine endometrial surveillance[112,158,159] 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. Because uterine bleeding is generally a sign of endometrial proliferation, any spotting or bleeding requires a thorough evaluation that may include transvaginal ultrasound (TVU) and/or endometrial biopsy.

Testosterone. Topical testosterone cream has been used for the treatment of vulvovaginal conditions, including lichen sclerosus and vestibulodynia, despite limited efficacy data.[160,161] Although not government approved for this indication, there are limited data supporting the use of vaginal testosterone cream for the treatment for GSM. A 4-week pilot trial of 20 postmenopausal women with breast cancer found that vaginal testosterone (150 μg and 300 μg) improved dyspareunia, vaginal dryness, and VMI without increasing estradiol; median testosterone level increased from 15.5 ng/dL to 21.5 ng/dL (P = .02).[162] A 12-week RCT in 76 menopausal women taking AIs after treatment for early stage breast cancer who reported vaginal dryness, dyspareunia, or reduced libido compared the low-dose estradiol vaginal ring with compounded vaginal testosterone cream. Symptoms of GSM and sexual desire improved in both treatment arms. The observation that levels of serum estradiol were increased in trial participants at baseline complicates interpretation of these findings.[163] Existing clinical trial data are insufficient to recommend the use of vaginal testosterone for GSM.[164] Longer and larger studies are needed to assess safety and efficacy.

Energy-based Therapies

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, 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.[165]

Vulvovaginal energy-based devices are thought to improve vaginal health by causing microtrauma, which induces collagen formation, angiogenesis, and epithelial thickening. The fractional CO2 laser has demonstrated safety and efficacy in tissues of the skin, face, and neck.[166–169] Using a probe adapted to the vagina, fractional CO2 vaginal laser therapy induces similar morphologic changes in the vagina, and data from small studies support improvement in GSM symptoms of vaginal dryness and dyspareunia.[170–178] Several RCTs have compared laser therapy to vaginal ET. Overall, no treatment was superior to another, and the studies were not designed to assess noninferiority.[179–182] Radiofrequency devices are nonablative and emit focused electromagnetic waves that heat the superficial layers of the tissue. Several RCTs evaluating the efficacy of energy-based devices in the treatment of GSM are in progress.

Safety. 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.[183] These treatments are costly and generally not covered by insurers.

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 as well as concerns about safety.[184–187] Additional randomized, prospective, sham-controlled trials of adequate size and scope are necessary before these therapies can be routinely recommended for treatment of GSM.

Treatment Considerations in Women With Breast Cancer

Treatment of GSM in women with breast cancer can be complicated by 1) adjuvant treatment (AIs or tamoxifen), which lower estrogen concentrations or antagonize estrogen effects; 2) product labeling; 3) limited clinical trial data in patients with breast cancer or survivors; and 4) absence of agreement between the oncology community and other practitioners involved in genitourinary and sexual healthcare. Many women with breast cancer and GSM will benefit from the regular use of vaginal moisturizers, lubricants for sexual activity, and PFPT. For persistent symptoms, other therapies may be beneficial, including topical lidocaine, low-dose vaginal ET, vaginal DHEA, ospemifene, and vaginal energy-based therapies.[188–191]

For women with breast cancer, low-dose vaginal ET is contraindicated according to FDA class labeling. However, off-label use of several products may be acceptable because of their very low systemic absorption.[192] Low-dose vaginal ET formulations, including the estradiol tablet, insert, and ring, result in serum estradiol within the postmenopausal range and similar to placebo.[145,146] Several organizations, including the American College of Obstetricians and Gynecologists, have endorsed the use of low-dose vaginal estrogens in women with breast cancer, including ER-positive disease. A systematic review and meta-analysis also suggests safety, based on the use of low-dose vaginal ET in survivors of breast cancer using concomitant AIs.[193] Many oncologists allow the use of low-dose vaginal ET or vaginal DHEA in their patients with breast cancer when GSM symptoms persist after trials of nonhormone interventions and QOL is adversely affected.

Use of vaginal DHEA for GSM in women with breast cancer is not contraindicated, but US labeling advises caution because estrogen is a metabolite of DHEA.[95] Although vaginal DHEA has not been studied in women with a history of breast cancer, levels of estradiol and testosterone remain within the postmenopause range.[194]

Ospemifene is not recommended for treatment of GSM in women with known or suspected breast cancer because the drug has not been adequately studied in this group. Preliminary data on ospemifene suggest both a decreased risk of incident breast cancer and a reduced risk of breast cancer recurrence with this therapy.[156]

Clinical trials of laser therapy for GSM in survivors of breast cancer provide limited evidence for safety and efficacy in this patient population.[195–197] These studies generally do not have either a positive or sham control, a shortcoming of many of the studies on these devices.

Education

Healthcare providers should educate women about GSM and the urogenital changes that often occur with menopause. Many women are unaware that vaginal dryness, recurrent UTIs, discomfort with sexual activity, and other GSM symptoms are a consequence of estrogen deficiency. Unlike VMS that typically improve with time, GSM symptoms often worsen in the absence of treatment. Women also may not know that effective and safe OTC and prescription therapies are available. Women who are sexually active are more likely to notice GSM symptoms and seek care, but sexually inactive women also will benefit from education about GSM. Women who are concerned about future urogenital function may consider preventive use of lubricants, moisturizers, vaginal dilators, or prescription therapies, but there is no evidence to support this approach. It is unknown whether treatment to preserve sexual function or prevent the future occurrence of GSM is indicated in the absence of urogenital symptoms.

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