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Genitourinary Syndrome of Menopause: Management Strategies for the Clinician

      Abstract

      Genitourinary syndrome of menopause (GSM), previously known as atrophic vaginitis or vulvovaginal atrophy, affects more than half of postmenopausal women. Caused by low estrogen levels after menopause, it results in bothersome symptoms, including vaginal dryness, itching, dyspareunia, urinary urgency and increased frequency, and urinary tract infections. Even though women with GSM can have sexual dysfunction that interferes with partner relationships, women are often embarrassed to seek treatment, and health care professionals do not always actively screen for GSM. As a result, GSM remains underdiagnosed and undertreated. Several effective treatments exist, but low-dose vaginal estrogen therapy is the criterion standard. It is effective and safe for most patients, but caution is suggested for survivors of hormone-sensitive cancers. Newer treatment options include selective estrogen receptor modulators, vaginal dehydroepiandrosterone, and laser therapy. Nonprescription treatments include vaginal lubricants, moisturizers, and dilators. Pelvic floor physical therapy may be indicated for some women with concomitant pelvic floor muscle dysfunction. Sex therapy may be helpful for women with sexual dysfunction. This concise review presents a practical approach to the evaluation and management of GSM for the primary care physician.

      Abbreviations and Acronyms:

      AI (aromatase inhibitor), DHEA (dehydroepiandrosterone), ET (estrogen therapy), FDA (US Food and Drug Administration), GSM (genitourinary syndrome of menopause), SERM (selective estrogen receptor modulator)
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      Learning Objectives: On completion of this article, you should be able to (1) describe the signs and symptoms of genitourinary syndrome of menopause (GSM), (2) list the hormonal and nonhormonal treatment strategies for GSM, and (3) determine appropriate follow-up of patients with GSM.
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      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Faubion is a consultant for Mithra Pharmaceuticals and Procter and Gamble. Mayo Clinic does not endorse specific products or services included in this article.
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      Genitourinary syndrome of menopause (GSM) is a common, underrecognized, and undertreated condition that results from decreased estrogen levels. Affecting nearly 50% of postmenopausal women, GSM also occurs in other low-estrogen states, such as postpartum, during lactation, and with certain medications (eg, aromatase inhibitors [AIs]).
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Other names for this condition include vulvovaginal atrophy, vaginal atrophy, and atrophic vaginitis.
      • Portman D.J.
      • Gass M.L.
      Vulvovaginal Atrophy Terminology Consensus Conference Panel
      Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and The North American Menopause Society.
      A change in terminology was proposed and endorsed by the North American Menopause Society and the International Society for the Study of Women's Sexual Health in 2014 to (1) acknowledge the involvement of not only the vulvar and vaginal tissues but also the lower urinary tract, (2) identify menopause as an etiologic factor, and (3) avoid the negative connotations associated with the term atrophy.
      • Portman D.J.
      • Gass M.L.
      Vulvovaginal Atrophy Terminology Consensus Conference Panel
      Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and The North American Menopause Society.
      Although vasomotor symptoms typically improve over time, GSM is chronic and progressive, and symptoms are unlikely to resolve without treatment.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Findings from the Real Women's Views of Treatment Options for Menopausal Vaginal Changes (REVIVE) survey,
      • Kingsberg S.A.
      • Wysocki S.
      • Magnus L.
      • Krychman M.L.
      Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey.
      involving 3046 postmenopausal women with symptoms of GSM, suggested a lack of awareness that these changes relate to the menopause transition. Further, 59% of respondents reported that their symptoms considerably decreased their enjoyment of sexual activity, and 23% reported an adverse effect on general enjoyment of life.
      • Kingsberg S.A.
      • Wysocki S.
      • Magnus L.
      • Krychman M.L.
      Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey.
      The Women's EMPOWER survey
      • Kingsberg S.A.
      • Krychman M.
      • Graham S.
      • Bernick B.
      • Mirkin S.
      The Women's EMPOWER survey: identifying women's perceptions on vulvar and vaginal atrophy and its treatment.
      queried 1858 community-dwelling US women and found that women did not bring up the topic with their health care professional because of embarrassment or concerns that the topic was inappropriate for conversation, but most were willing to try a product for symptom relief and would welcome information and treatment suggestions from their health care professional. The Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) survey reported on 1000 married or cohabitating North American menopausal women with vaginal discomfort and their male partners and the impact of vaginal dryness and low-dose vaginal estrogen therapy (ET) on various parameters.
      • Simon J.A.
      • Nappi R.E.
      • Kingsberg S.A.
      • Maamari R.
      • Brown V.
      Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on North American postmenopausal women and their partners.
      Results revealed that the women and their partners believed that vaginal discomfort had a considerable impact on intimacy. Women avoided intimacy because of vaginal discomfort (58%), experienced loss of libido (64%), and experienced sexual pain (64%). The majority of male partners believed that vaginal dryness caused avoidance of intimacy by their partners (78%), loss of libido (52%), and painful sex (59%). The use of low-dose vaginal ET was associated with less painful sex, greater satisfaction with sex, and an improved sex life.
      • Simon J.A.
      • Nappi R.E.
      • Kingsberg S.A.
      • Maamari R.
      • Brown V.
      Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on North American postmenopausal women and their partners.

      Presentation and Evaluation

      Genitourinary syndrome of menopause is a clinical diagnosis, and laboratory testing is usually unnecessary. Although some women with mild GSM remain asymptomatic, many women report symptoms such as vaginal dryness, burning, irritation, decreased lubrication with sexual activity, and dyspareunia with resultant sexual dysfunction.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Urinary symptoms of GSM may include frequency, dysuria, and increased risk for urinary tract infections.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      For some women, symptoms can be severe enough to preclude penetrative sexual activity and to cause discomfort even with sitting or wiping. In women taking AIs, symptoms are more common and may be particularly severe.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Changes on examination include scant pubic hair, loss of the labial fat pad, thinning and resorption of the labia minora, narrowing of the introitus, and increased vaginal pH.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Internal examination findings include reduced vaginal caliber; smooth, shiny, pale mucosa with loss of folds; and a cervix flush with the vaginal vault. With inflammation, the vagina may appear erythematous, develop petechiae, and bleed easily.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      A pelvic examination can be helpful to exclude other vulvar and vaginal conditions that may present with symptoms similar to those of GSM, including irritant, infectious, or inflammatory vaginitis; dermatoses; and neoplasia.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.

      Management of GSM

      Lubricants and Moisturizers

      Lubricants and moisturizers are used for sexual comfort and pleasure and are particularly useful for women with mild to moderate vaginal dryness and for those who choose not to use vaginal ET.
      • Edwards D.
      • Panay N.
      Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?.
      Lubricants provide short-term relief of vaginal dryness and discomfort with sexual activity. They may be water, silicone, or oil based and are applied to the vulva, vagina, or penis (or to all 3) before sexual activity. Water-based lubricants have the advantage of being nonstaining and are associated with fewer genital symptoms than the silicone-based lubricants.
      • Edwards D.
      • Panay N.
      Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?.
      There are limited data on the safety of oils (eg, olive oil, coconut oil, and mineral oil) and petrolatum used as lubricants, although there are concerns about effects on sperm motility, condom integrity, and increased risk for Candida species colonization and bacterial vaginosis with the use of these products.
      • Sandhu R.S.
      • Wong T.H.
      • Kling C.A.
      • Chohan K.R.
      In vitro effects of coital lubricants and synthetic and natural oils on sperm motility.
      • Voeller B.
      • Coulson A.H.
      • Bernstein G.S.
      • Nakamura R.M.
      Mineral oil lubricants cause rapid deterioration of latex condoms.
      • Brown J.M.
      • Hess K.L.
      • Brown S.
      • Murphy C.
      • Waldman A.L.
      • Hezareh M.
      Intravaginal practices and risk of bacterial vaginosis and candidiasis infection among a cohort of women in the United States.
      Vaginal moisturizers are used on a regular basis to maintain vaginal moisture (daily or every 2-3 days as needed on the basis of symptom severity). They provide longer-term relief by increasing mucosal moisture and reducing pH.
      • Edwards D.
      • Panay N.
      Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?.
      Hyaluronic acid vaginal gel, used every 3 days, has been associated with improvement in symptoms of vaginal dryness comparable to that seen with estriol cream without a change in pH.
      • Chen J.
      • Geng L.
      • Song X.
      • Li H.
      • Giordan N.
      • Liao Q.
      Evaluation of the efficacy and safety of hyaluronic acid vaginal gel to ease vaginal dryness: a multicenter, randomized, controlled, open-label, parallel-group, clinical trial.
      Vaginal lubricants and moisturizers can be used as needed in combination with other GSM treatments.

      Low-Dose Vaginal ET

      Low-dose vaginal ET is the preferred pharmacological treatment if symptomatic GSM is unresponsive to nonprescription therapies.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      It is more effective and safer than systemic ET for treatment of GSM.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      In fact, women receiving systemic ET for other menopausal symptoms often have persistent GSM symptoms requiring supplemental vaginal ET.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      With low-dose vaginal ET, systemic estrogen absorption is minimal, and serum estradiol levels (according to studies using older assays) remain in the postmenopausal range.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Multiple US Food and Drug Administration (FDA)–approved vaginal estrogen products with similar efficacy are available (Table 1),
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      and the choice is determined predominantly by patient preference. Estrogen creams provide a soothing and moisturizing effect, but some patients find them messy and dislike the reusable applicators.
      • Kingsberg S.A.
      • Krychman M.
      • Graham S.
      • Bernick B.
      • Mirkin S.
      The Women's EMPOWER survey: identifying women's perceptions on vulvar and vaginal atrophy and its treatment.
      Also, the amount of cream inserted in the vagina varies because it is not packaged as a dosing unit. This feature may be unacceptable when low-dose vaginal ET is required (eg, in breast cancer survivors). Vaginal estradiol tablets (10-μg dose) may be preferred in situations requiring more controlled dosing of vaginal ET. With creams and tablets, women may use daily dosing for the first 2 weeks followed by twice-weekly maintenance dosing. Ideally, women should be treated with the lowest dose and frequency of vaginal ET that effectively manages their symptoms.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Table 1Hormonal Therapy for Management of GSM
      Adapted from Menopause,
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      with permission.
      TreatmentProductDosageComments
      InitialMaintenance
      Vaginal cream
       Estradiol-17βEstrace0.5-1 g daily for 2 wk0.5-1 g 1-3 times weeklyFDA-approved dose is higher loading dose (2-4 g daily; maintenance dose, 1 g 1-3 times weekly)
       Conjugated estrogensPremarin0.5-1 g daily for 2 wk0.5-1 g 1-3 times weeklyFDA-approved dose is higher and administration is cyclical (for GSM: 0.5-2 g daily for 21 d and then off for 7 d; for dyspareunia: 0.5 g daily for 21 d and then off for 7 d or 0.5 g twice weekly)
      Vaginal insert
       Estradiol hemihydrateVagifem, Yuvafem10-μg insert once daily for 2 wk1 twice weekly
       Estradiol-17β softgel capsulesTX-004HR4, 10, or 25 μg daily for 2 wk1 twice weeklyThis product is not yet FDA approved
       DHEA (prasterone)Intrarosa6.5 mg once daily6.5 mg once daily
      Vaginal ring
       Estradiol-17βEstringInsert for 90 d (2 mg releases approximately 7.5 μg daily)Change every 90 d
       Estradiol acetateFemringInsert for 90 d (12.4 mg or 24.8 mg releases 0.05 mg or 0.1 mg daily, respectively)Change every 90 dThis product is delivered vaginally but it provides systemic hormone levels to treat VMS and GSM
      SERM
       OspemifeneOsphena60 mg daily60 mg dailyFDA approved for dyspareunia
      DHEA = dehydroepiandrosterone; FDA = US Food and Drug Administration; GSM = genitourinary syndrome of menopause; SERM = selective estrogen receptor modulator; VMS = vasomotor symptoms; ellipses = no comment.
      Sustained-release estradiol vaginal rings, which can be inserted and removed by patients, are effective for 90 days. The lower-dose ring (Estring, 2 mg) releases approximately 7.5 μg daily and is useful for GSM only; the higher-dose ring (Femring, 12.4 mg or 24.8 mg releases 0.05 mg or 0.1 mg daily, respectively) produces systemic estradiol levels adequate to treat GSM and vasomotor symptoms.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      The ring is especially useful for women who prefer not to use a vaginal estrogen product every few days.
      A vaginal softgel capsule containing solubilized estradiol-17β (4-, 10-, and 25-μg doses) is an emerging treatment option for GSM (it is not yet FDA approved). It provided statistically significant improvement in GSM symptoms compared with placebo with minimal systemic absorption in a 12-week, randomized placebo-controlled trial (used daily for 2 weeks and then twice weekly).
      • Constantine G.D.
      • Simon J.A.
      • Pickar J.H.
      • et al.
      REJOICE Study Group
      The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy.
      • Simon J.A.
      • Archer D.F.
      • Constantine G.D.
      • et al.
      A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: efficacy and pharmacokinetic data review.
      Maximum serum concentrations of estradiol in the softgel capsule group were lower when compared with estradiol tablets delivering an equivalent dose (P=.019 for 10-μg tablet; P<.001 for 25-μg tablet).
      • Pickar J.H.
      • Amadio J.M.
      • Bernick B.A.
      • Mirkin S.
      Pharmacokinetic studies of solubilized estradiol given vaginally in a novel softgel capsule.
      The estradiol vaginal capsule may be useful for women who dislike creams or who want to minimize exposure to systemic estrogen.
      Women may notice improvement in symptoms within a few weeks of initiating treatment,
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      • Simon J.A.
      • Archer D.F.
      • Constantine G.D.
      • et al.
      A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: efficacy and pharmacokinetic data review.
      but many require 8 to 12 weeks for the full benefit of therapy, which can be continued as long as needed to manage symptoms.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Observational data reveal no evidence of harm with extended use, but clinical trial safety data are limited to 1 year.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      A progestogen is typically not required for endometrial protection in women receiving low-dose vaginal ET.
      The 2017 hormone therapy position statement of The North American Menopause Society.
      However, periodic endometrial surveillance or progestogen use is a consideration for women at high risk for endometrial cancer or those who are using vaginal ET in doses that are higher than usual.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Clinical trial data are lacking on the safety of low-dose vaginal ET in survivors of hormone-dependent cancers (breast and endometrial cancers). In general, nonhormonal treatments are preferred initial strategies, but after a careful discussion of the potential benefits and risks, low-dose vaginal ET, possibly for a short duration, may be considered in women with refractory symptoms affecting their quality of life.
      The 2017 hormone therapy position statement of The North American Menopause Society.
      The goal of AI therapy is to reduce circulating estradiol levels, so low-dose vaginal ET should be used cautiously in women receiving AI therapy for breast cancer treatment. Small but significant increases in estradiol levels have been found in women treated with AIs while they use the 25-μg estradiol tablet (no longer available) or the estradiol ring.
      • Kendall A.
      • Dowsett M.
      • Folkerd E.
      • Smith I.
      Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors.
      • Wills S.
      • Ravipati A.
      • Venuturumilli P.
      • et al.
      Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator.
      Women using the new estradiol vaginal capsule at the 4-μg dose did not have any differences in mean serum estradiol concentrations compared with placebo, but women using the 10-μg dose had a difference at day 1, with no difference by day 14.
      • Simon J.A.
      • Archer D.F.
      • Constantine G.D.
      • et al.
      A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: efficacy and pharmacokinetic data review.
      Vaginal ET does not seem to increase the risk of venous thromboembolism, but data on high-risk patients are lacking.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Vaginal ET is contraindicated in any woman with undiagnosed vaginal bleeding. Similarly, any woman who reports vaginal bleeding during treatment with vaginal ET should undergo evaluation, including pelvic imaging and endometrial biopsy if indicated.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.

      Selective Estrogen Receptor Modulators

      Selective estrogen receptor modulators (SERMs) are synthetic nonsteroidal agents that exert variable mixed estrogen agonist and antagonist effects on target tissues.
      • Pinkerton J.V.
      • Stanczyk F.Z.
      Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy.
      Of the currently available SERMs, only ospemifene is FDA approved for the treatment of moderate to severe dyspareunia caused by GSM in menopausal women.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Ospemifene, when given orally at a dose of 60 mg daily, exerts estrogenic effects on vulvovaginal tissues and results in acidic vaginal pH and improvements in the vaginal maturation index and dyspareunia.
      • Portman D.J.
      • Bachmann G.A.
      • Simon J.A.
      Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy.
      Although ospemifene does not appear to stimulate breast tissue,
      • Berga S.L.
      Profile of ospemifene in the breast.
      • Burich R.A.
      • Mehta N.R.
      • Wurz G.T.
      • et al.
      Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model.
      • Pinkerton J.V.
      • Thomas S.
      Use of SERMs for treatment in postmenopausal women.
      its safety in women with or at high risk for breast cancer has yet to be established. Ospemifene is an option for management of dyspareunia in postmenopausal women and may be particularly appealing for those who are unwilling or unable to use low-dose vaginal estrogen.
      None of the other available SERMs are FDA approved for treatment of GSM. These SERMs include tamoxifen (approved for breast cancer prevention and treatment), raloxifene (approved for osteoporosis and breast cancer treatment), and bazedoxifene (approved for use in combination with conjugated equine estrogens for treatment of vasomotor symptoms and for osteoporosis prevention).
      • Pinkerton J.V.
      • Stanczyk F.Z.
      Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy.
      Tamoxifen exerts mixed vaginal effects and may cause dyspareunia, increased vaginal discharge, or vaginal dryness.
      • Pinkerton J.V.
      • Stanczyk F.Z.
      Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy.
      Raloxifene and bazedoxifene do not exert any direct positive effects on the vagina.
      • Pinkerton J.V.
      • Stanczyk F.Z.
      Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy.
      However, the combination of bazedoxifene and conjugated equine estrogens (20/0.45 mg daily) has improved symptoms and signs of GSM without causing endometrial hyperplasia.
      • Kagan R.
      • Williams R.S.
      • Pan K.
      • Mirkin S.
      • Pickar J.H.
      A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women.
      • Lobo R.A.
      • Pinkerton J.V.
      • Gass M.L.
      • et al.
      Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile.
      Lasofoxifene, a third-generation SERM currently under development and not approved by the FDA, has been reported to prevent bone loss and is effective for GSM.
      • Pinkerton J.V.
      • Stanczyk F.Z.
      Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy.

      Vaginal Dehydroepiandrosterone

      Dehydroepiandrosterone (DHEA) is a steroid prohormone in the biosynthetic pathway of testosterone and estradiol. Short-term clinical trials with daily use of vaginal DHEA have found improvements in GSM symptoms (including dyspareunia), vaginal pH, and the vaginal maturation index.
      • Labrie F.
      • Archer D.F.
      • Bouchard C.
      • et al.
      Intravaginal dehydroepiandrosterone (prasterone), a highly efficient treatment of dyspareunia.
      • Labrie F.
      • Archer D.F.
      • Koltun W.
      • et al.
      VVA Prasterone Research Group
      Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause.
      Vaginal DHEA is thought to exert its effect by local conversion to testosterone and estradiol; it has not been found to increase systemic steroid hormone levels, presumably because of local inactivation.
      • Labrie F.
      • Archer D.F.
      • Koltun W.
      • et al.
      VVA Prasterone Research Group
      Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause.
      Therefore, it may be a safer alternative to vaginal ET in patients with contraindications to estrogen use (eg, breast cancer survivors). Additionally, with the lack of the aromatase enzyme in the endometrium, vaginal DHEA is not converted to estradiol in the endometrium and does not exert any endometrial proliferative effects.
      • Portman D.J.
      • Labrie F.
      • Archer D.F.
      • et al.
      other participating members of VVA Prasterone Group
      Lack of effect of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women.
      Used as a daily vaginal insert, DHEA (Intrarosa, 6.5 mg), was recently approved by the FDA for the treatment of GSM.

      Laser Treatments

      Laser therapy for GSM has been tested in smaller, uncontrolled clinical trials with positive results.
      • Arunkalaivanan A.
      • Kaur H.
      • Onuma O.
      Laser therapy as a treatment modality for genitourinary syndrome of menopause: a critical appraisal of evidence.
      Although the carbon dioxide laser has been cleared by the FDA for “incision, excision, ablation, vaporization, and coagulation of body soft tissues in medical specialties, including aesthetic (dermatology and plastic surgery), podiatry, otolaryngology (ENT), gynaecology” and other specialties and the YAG laser has been cleared for “incision, excision, ablation, vaporization of soft tissue for General Dermatology, Dermatologic and General Surgical procedures for coagulation and hemostasis,” vulvovaginal atrophy or GSM is not specifically listed as an indication for treatment.
      American College of Obstetricians and Gynecologists, American Congress of Obstetricians and Gynecologists
      Position statement: fractional laser treatment of vulvovaginal atrophy and U.S. Food and Drug Administration clearance.
      The microablative carbon dioxide laser used for vaginal epithelial resurfacing activates heat shock proteins that in turn activate growth factors, resulting in an increase in vascularity, collagen, extracellular matrix production, and thickness of vaginal epithelium.
      • Stefano S.
      • Stavros A.
      • Massimo C.
      The use of pulsed CO2 lasers for the treatment of vulvovaginal atrophy.
      In a 12-week single-group study involving 50 women, 3 carbon dioxide pulsed laser treatments were administered 1 month apart, with results indicating statistically significant improvements in self-reported vaginal dryness, burning, itching, dyspareunia, and dysuria and in Vaginal Health Index scores (examiner assessments of elasticity, fluid secretion type, pH, epithelial mucosa, and moisture), with few reported adverse effects.
      • Salvatore S.
      • Nappi R.E.
      • Zerbinati N.
      • et al.
      A 12-week treatment with fractional CO2 laser for vulvovaginal atrophy: a pilot study.
      The erbium:YAG laser has also been studied for GSM. In an 18-month study with 50 women, when laser treatment was compared with intravaginal estriol, the laser treatment improved symptoms of GSM with minimal adverse effects, and the benefits were more pronounced and longer lasting compared with estriol.
      • Gaspar A.
      • Brandi H.
      • Gomez V.
      • Luque D.
      Efficacy of Erbium:YAG laser treatment compared to topical estriol treatment for symptoms of genitourinary syndrome of menopause.
      The large multicenter Vaginal Erbium Laser Academy Study (VELAS)
      • Gambacciani M.
      • Torelli M.G.
      • Martella L.
      • et al.
      Rationale and design for the Vaginal Erbium Laser Academy Study (VELAS): an international multicenter observational study on genitourinary syndrome of menopause and stress urinary incontinence.
      is evaluating the safety and efficacy of laser for treatment of GSM and stress urinary incontinence.
      Longer-term safety and efficacy studies using sham controls are needed before laser treatments can be recommended as a standard therapy for GSM.

      Other Therapeutic Considerations

      Education is important so that women know about the genitourinary changes that occur with the loss of estrogen associated with menopause. Patients should be advised that GSM symptoms are unlikely to improve without treatment, and counseling should include a review of treatment options, both nonhormonal and hormonal. Women who are sexually active are often aware of these gradual changes, which may cause discomfort with sexual activity, but sexually inactive women who have GSM and who resume sexual activity may be surprised that it is painful (or not even possible).
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Regular, painless sexual activity can help maintain vaginal health. A vibrator can be used therapeutically to stimulate blood flow and maintain vaginal function in women with or without a partner.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      Similarly, either a lubricated vibrator or vaginal dilator can be used to gently stretch the vaginal tissues. In women who experience vaginismus (ie, the involuntary contraction of the muscles surrounding the vagina), the progressive use of vaginal dilators with relaxation and mindfulness exercises can facilitate reinitiation of painless penetrative sexual activity.
      • Zarski A.C.
      • Berking M.
      • Fackiner C.
      • Rosenau C.
      • Ebert D.D.
      Internet-based guided self-help for vaginal penetration difficulties: results of a randomized controlled pilot trial.
      Pelvic floor physical therapy, ideally provided by a physical therapist with specialized training in pelvic floor disorders, may be useful for treatment of women with nonrelaxing or high-tone pelvic floor muscle dysfunction triggered by painful sexual activity related to GSM.
      • Faubion S.S.
      • Shuster L.T.
      • Bharucha A.E.
      Recognition and management of nonrelaxing pelvic floor dysfunction.
      Topical lidocaine applied to the introitus a few minutes before sexual activity has reduced pain with sexual activity in breast cancer survivors and may serve as an adjunct to other therapies (eg, vaginal moisturizers, lubricants, and physical therapy) for management of GSM.
      • Goetsch M.F.
      • Lim J.Y.
      • Caughey A.B.
      A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial.
      Table 2 summarizes nonhormonal treatment options.
      Table 2Nonhormonal Treatment Strategies for GSM
      Treatment strategySpecific therapyTypical useComments
      EducationProvide education on potential vulvar and vaginal changes associated with menopause or other low-estrogen states

      Offer therapy as indicated
      General patient educationEducation should be offered to women regardless of partner status

      Regular, painless sexual activity or vaginal stimulation can help maintain sexual function
      LubricantsExamples of lubricants: YES, JO, Good Clean Love, Pink, and UberlubeUsed as needed for sexual activityUsed to increase comfort and pleasure

      Avoid irritants (eg, glycerin, parabens, and propylene glycol)

      Can be used with other therapies (hormonal and nonhormonal)
      MoisturizersExamples of moisturizers: Replens, RepHresh, Sliquid Satin, and Hyalo GynUsed daily or every few days on a regular basis to maintain vulvar and vaginal moistureMimic normal vaginal secretions

      Do not reverse cellular and pH changes of GSM

      Can be used with other therapies (hormonal and nonhormonal)
      Use of dilators and vibratorsMultiple types availableUsed as neededGently stimulate and stretch the vulvar and vaginal tissues to maintain function
      Pelvic floor physical therapyProvide education as indicated on kinesthetic awareness, pelvic floor muscle relaxation, manual therapies, and biofeedbackUsed as needed for nonrelaxing pelvic floor muscle dysfunctionIdentify a physical therapist who specializes in pelvic floor disorders (http://www.womenshealthapta.org/)
      Section on Women's Health website.
      Topical lidocaine4% aqueous lidocaineApplied to the vestibule a few minutes before sexual activityCan be used as an adjunct to other therapies, including lubricants, moisturizers, and physical therapy
      Laser therapyCarbon dioxide laser

      Erbium:YAG laser
      Administered as a series of 3 treatments a few weeks apartUse is limited by a lack of studies examining long-term safety and efficacy and comparing laser therapy with estrogen therapy and sham control
      GSM = genitourinary syndrome of menopause.

      Follow-up

      Low-dose vaginal ET is a highly effective therapy for GSM, and most women respond well to treatment. In nonresponders, adherence must be assessed. An analysis of US prescription renewal data revealed that a large proportion of women discontinued vaginal ET within 2 to 4 months after initiating therapy.
      • Portman D.
      • Shulman L.
      • Yeaw J.
      • et al.
      One-year treatment persistence with local estrogen therapy in postmenopausal women diagnosed as having vaginal atrophy.
      Common reasons for discontinuation included messiness of the creams, inconvenience of the applicator, vaginal discharge, and concerns about long-term safety.
      • Kingsberg S.A.
      • Krychman M.
      • Graham S.
      • Bernick B.
      • Mirkin S.
      The Women's EMPOWER survey: identifying women's perceptions on vulvar and vaginal atrophy and its treatment.
      Women who remain symptomatic despite the use of low-dose vaginal ET should be reevaluated with consideration given to alternative or concomitant diagnoses, such as infection, inflammatory or autoimmune diseases, dermatoses, allergic conditions, neoplasia, vulvodynia, or other medical or psychological contributors.
      Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society.
      In women with ongoing deep dyspareunia despite adequate treatment of GSM, nonrelaxing pelvic floor muscle dysfunction should be considered, and evaluation and treatment by a physical therapist is indicated.
      • Faubion S.S.
      • Shuster L.T.
      • Bharucha A.E.
      Recognition and management of nonrelaxing pelvic floor dysfunction.
      Genitourinary syndrome of menopause with or without pelvic floor muscle dysfunction can adversely affect sexual function, and referral to a sex therapist may also be useful.
      • Faubion S.S.
      • Shuster L.T.
      • Bharucha A.E.
      Recognition and management of nonrelaxing pelvic floor dysfunction.

      Conclusion

      Genitourinary syndrome of menopause is underrecognized and undertreated and seriously affects quality of life, but many effective treatment strategies are available. Low-dose vaginal ET is the criterion standard therapy, but other treatments are also effective, including ospemifene and intravaginal DHEA. The laser holds promise, but additional studies are needed. Health care professionals should ask menopausal women about symptoms and offer education and therapy as indicated.

      Supplemental Online Material

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