By Rebecca H. Allen, MD, MPH
Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she receives grant/research support from Bayer and is a consultant for Merck.
Vulvovaginal atrophy, now known as the genitourinary syndrome of menopause (GSM), occurs with the decline of estrogen in the menopausal period. Due to the loss of estrogen, the vulvovaginal tissue becomes thinner, the vagina becomes more alkaline, and vaginal secretions can decrease.1 Many postmenopausal women report symptoms related to vulvovaginal atrophy, including vaginal dryness, dyspareunia, vaginal burning or itching, vaginal discharge, and urinary tract symptoms.2 Of course, the condition also occasionally can occur during other low estrogen states, such as lactation and hypothalamic amenorrhea, or among women taking antiestrogenic drugs, often for breast cancer treatment. Women may be asymptomatic or reluctant to discuss the problem with their providers.3 Whether a woman is sexually active does not always correlate with the degree of symptoms she may experience.
Typically, providers can diagnose vulvovaginal atrophy by physical exam alone. Findings may include labia minora resorption; loss of hymenal remnants; loss of vaginal rugae; fragile, pale, and dry vaginal epithelium; and shortened vagina. The cervix may become flush with the vaginal vault, with the cervical os difficult to identify.2 When the vagina appears inflamed, the term atrophic vaginitis is used. Since lactobacilli depend on an estrogen-replete environment to thrive and prosper, the pH of the vagina often is elevated above 5.0 and saline wet prep reveals relative acellularity with the proportion of parabasal cells increased.3 In research studies, investigators measure the maturation index, which is the proportion of parabasal, intermediate, and superficial vaginal epithelial cells in each 100 cells on a saline wet prep. Parabasal cells signify the absence of estrogen. Thus, premenopausal women usually have no parabasal cells, whereas women in menopause have a majority of parabasal cells.4
The treatment of vulvovaginal atrophy often depends on the severity of the condition. Treatments include vaginal lubricants, vaginal moisturizers, and local vaginal estrogen for patients who do not need or want systemic estrogen therapy. Vaginal moisturizers include components that adhere to the vagina and allow intermittent dosing, while vaginal lubricants typically are used before intercourse.3 First-line treatment for milder symptoms often includes vaginal lubricants to be used at the time of sexual intercourse to reduce friction on delicate tissue. If one lubricant does not work or causes irritation, the patient can try another lubricant (e.g., water-based vs. silicone-based). Coconut oil is another option that now is used widely for vulvovaginal lubrication. Often, this is recommended for patients with vulvodynia. Patients also can opt for vaginal moisturizers, which are used several times a week unrelated to the timing of intercourse. Vaginal sexual intercourse can be an important part of therapy, as it maintains vaginal health by regularly increasing blood flow to the vagina. Masturbation and sexual toys can be used if a patient does not have a partner.4
Because vaginal lubricants and moisturizers offer some symptomatic relief but do not reverse the maturation index of the vagina, these agents can fail women with more severe symptoms. In these cases, vaginal estrogen or other treatments are needed.3 Vaginal estrogen is safe and does not increase the risk of cardiovascular disease, breast cancer, endometrial cancer, or all-cause mortality.5,6 Vaginal estrogen treatments include 4 mcg or 10 mcg estradiol tablets, a three-month estradiol vaginal ring that releases 7.5 mcg daily, and estradiol or conjugated estrogen cream. (See Table 1.) The most recent estrogen product on the market (Imvexxy) contains estradiol. The novel features of this product are that it does not require an applicator and it is suspended in coconut oil. It also is available in two low doses of estrogen (4 mcg or 10 mcg).
Table 1: Vaginal Products for the Genitourinary Syndrome of Menopause
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Premarin cream
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0.625 mg conjugated estrogens per gram of cream
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0.5 g of cream intravaginally administered nightly with reusable applicator for two weeks, then twice weekly for maintenance. Note: this dose is lower than that on the label but avoids too much systemic absorption of estrogen.
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Estrace cream
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100 mcg estradiol per gram of cream
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0.5 g of cream intravaginally administered nightly with reusable applicator for two weeks, then twice weekly for maintenance. Note: this dose is lower than that on the label but avoids too much systemic absorption of estrogen.
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Vagifem/Yuvafem
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10 mcg estradiol per vaginal tablet
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Single-use, disposable applicator used to insert one tablet intravaginally daily for two weeks, followed by twice weekly.
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Imvexxy
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4 or 10 mcg estradiol per capsule
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Capsule inserted intravaginally with fingers daily for two weeks, followed by twice weekly.
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Estring
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7.5 mcg estradiol per day, released over 90 days
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Ring is inserted into the vagina and remains in place for 90 days and then replaced with a new ring. May be patient- or provider-administered similar to a pessary.
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Intrarosa
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Dehydroepiandrosterone (prasterone) 6.5 mg
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Single-use, disposable applicator used to insert one tablet intravaginally daily.
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The authors of a Cochrane Review concluded that vaginal estrogen in different forms was superior to placebo for the treatment of GSM (vulvovaginal atrophy), although the quality of the evidence was low, mostly because of small sample sizes.7 In addition, the authors of a systematic review concluded that “all commercially available vaginal estrogens effectively relieve common vulvovaginal atrophy-related complaints.”8 With correct dosing, the systemic absorption of vaginal estrogen remains in the postmenopausal range and does not require a progestin for the prevention of endometrial hyperplasia and cancer.3 The use of vaginal estrogen in women with a history of breast cancer should be coordinated with the patient’s oncologist.
Prasterone (Intrarosa) is a new non-estrogen topical product on the market for GSM that is approved for the treatment of moderate-to-severe dyspareunia due to menopause. There have been no head-to-head trials of prasterone with vaginal estrogen. One study showed that prasterone was superior to placebo and improved female sexual function index scores after 12 weeks of therapy.9 Prasterone is supposed to work through aromatization of androstenedione and testosterone locally in the vagina to estrone and estradiol. Because of its daily dosing and lack of known superiority to estrogen, most experts view this as second-line treatment for patients who do not want to use estrogen. In addition, newer brand name products, Intrarosa and Imvexxy, may have less insurance coverage compared to more established estrogen products, limiting patient access.
Ospemifene is an oral agent that is indicated specifically for the treatment of moderate-to-severe dyspareunia caused by GSM.1 Approved in 2013, ospemifene is a selective estrogen receptor modulator that acts as an estrogen agonist in the vagina but does not appear to stimulate breast and endometrial tissue.10 This daily oral option typically is considered for women who prefer not to or cannot use a vaginal product. Similar to prasterone, there have not been any head-to-head trials comparing ospemifene with vaginal estrogen. Side effects include hot flashes, with one trial reporting a 7% rate of hot flashes with ospemifene compared to 4% in the placebo arm.10 All selective estrogen receptor modulators have the potential to increase the risk of venous thromboembolism. Neither prasterone nor ospemifene has been demonstrated to be safe for breast cancer patients.
Finally, the use of vaginal laser therapy (microablative fractional laser: carbon dioxide, erbium, YAG, or hybrid technologies) for GSM has been shown to improve symptoms associated with GSM, but it remains controversial.11,12 Most providers recognize this treatment as the MonaLisa Touch laser. The technology was introduced prior to any randomized, placebo-controlled trials showing safety and efficacy over the long-term. The mechanism of action is to create microabrasions in the vaginal epithelium that then stimulate improved vascular supply and collagen development, thickening the vaginal epithelium.4 In July 2018, the U.S. Food and Drug Administration (FDA) cautioned that it has not approved any energy-based devices to treat vulvovaginal atrophy or vaginal laxity and that the use of these devices could cause vaginal burns, scarring, and dyspareunia.13 The American College of Obstetricians and Gynecologists and North American Menopause Society agreed with the FDA’s cautionary stance, stating that although preliminary data are promising, more research is needed before these devices are used routinely in practice.14,15 There have been case reports of persistent dyspareunia, vaginal insertion pain, vaginal stenosis, and vaginal lacerations during intercourse after vaginal laser treatment.16 Because of these safety concerns and the lack of definitive research proving safety and efficacy, women should be counseled about other options prior to resorting to vaginal laser therapy.12 Since laser therapy to the vagina is considered cosmetic by most insurance companies and is not FDA-approved, this therapy rarely is covered by health insurers and patients must pay out of pocket. Practitioners usually recommend yearly treatments to maintain the beneficial effects of this laser therapy.
As with many clinical conditions, the spectrum of GSM requires the clinician to consider the effect on the patient’s quality of life. Although many symptoms are pacified effectively with situational lubricants and regular moisturizers, local estrogen is a safe, effective, and affordable way to treat the vulvovaginal changes of menopause.
REFERENCES
- American College of Obstetricians and Gynecologists Practice Bulletin No. 141. Management of menopausal symptoms. January 2014.
- Minkin MJ, Reiter S, Maamari R. Prevalence of postmenopausal symptoms in North America. Menopause 2015;22:1231-1238.
- Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society. Menopause 2013;20:888-902.
- Gandhi J, Chen A, Dagur G, et al. Genitourinary syndrome of menopause: An overview of clinical manifestations, pathophysiology, etiology, evaluation, and management. Am J Obstet Gynecol 2016;215:704-711.
- Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause 2018;25:11-20.
- Bhupathiraju SN, Grodstein F, Stampfer MJ, et al. Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause 2018; Dec. 17. doi: 10.1097/GME.0000000000001284. [Epub ahead of print].
- Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database System Rev 2016;(8):CD001500.
- Rahn DD, Carberry C, Sanses TV, et al. Vaginal estrogen for genitourinary syndrome of menopause: A systematic review. Obstet Gynecol 2014;124:1147-1156.
- Labrie F, Derogatis L, Archer DF, et al. Effect of intravaginal prasterone on sexual dysfunction in postmenopausal women with vulvovaginal atrophy. J Sex Med 2015;12:2401-2412.
- Portman DJ, Bachmann GA, Simon JA; Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 2013;20:623-630.
- Arunkalaivanan A, Kaur H, Onuma O. Laser therapy as a treatment modality for genitourinary syndrome of menopause: A critical appraisal of evidence. Int Urogynecol J 2017;28:681-685.
- Kaunitz AM, Pinkerton JV, Manson JE.. Women harmed by vaginal laser for treatment of GSM — the latest casualties of fear and confusion surrounding hormone therapy. Menopause 2019; Feb. 19. doi: 10.1097/GME.0000000000001313. [Epub ahead of print].
- U.S. Food and Drug Administration. FDA Warns Against Use of Energy-Based Devices to Perform Vaginal ‘Rejuvenation’ or Vaginal Cosmetic Procedures: FDA Safety Communication. Available at: https://bit.ly/2LOGN4h. Accessed Feb. 25, 2019.
- American College of Obstetricians and Gynecologists Position Statement. Fractional Laser Treatment of Vulvovaginal Atrophy and U.S. Food and Drug Administration Clearance. Available at: https://bit.ly/2HtIvFz. Accessed Feb. 25, 2019.
- North American Menopause Society. FDA Mandating Vaginal Laser Manufacturers Present Valid Data Before Marketing. Available at: https://bit.ly/2OEWzgz. Accessed Feb. 25, 2019.
- Gordon C, Gonzales S, Krychman ML. Rethinking the techno vagina: A case series of patient complications following vaginal laser treatment for atrophy. Menopause 2019; Jan. 14. doi: 10.1097/GME.0000000000001293. [Epub ahead of print].
