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Original Investigation
May 2018

Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial

Author Affiliations
  • 1Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston
  • 2Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts
  • 3Department of Obstetrics and Gynecology, University of Washington, Seattle
  • 4Department of Medicine, University of Minnesota, Minneapolis
  • 5Department of Epidemiology and Community Health, University of Minnesota, Minneapolis
  • 6Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 7Kaiser Permanente Washington Health Research Institute, Seattle
  • 8Department of Medicine, Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota
  • 9Department of Family Medicine and Public Health, University of California at San Diego, La Jolla
  • 10Division of Research, Kaiser Permanente of Northern California, Oakland, California
JAMA Intern Med. 2018;178(5):681-690. doi:10.1001/jamainternmed.2018.0116
Key Points

Question  Does 12-week treatment with vaginal 10-μg estradiol tablet or vaginal moisturizer improve postmenopausal vulvovaginal symptoms more than placebo?

Findings  In a randomized clinical trial of 302 postmenopausal women with moderate-to-severe vulvovaginal symptoms, vaginal 10-μg estradiol tablet plus placebo gel and vaginal moisturizer plus placebo tablet were not more efficacious than dual placebo at reducing symptom severity or improving sexual function.

Meaning  Shared decision making for treatment of postmenopausal vulvovaginal symptoms can be based on cost and patient formulation preference; vaginal estradiol tablets appear not to add benefit beyond vaginal gel or moisturizer.


Importance  Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments.

Objective  To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms.

Design, Setting, and Participants  This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration.

Interventions  Vaginal 10-μg estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100).

Main Outcomes and Measures  The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score–Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH.

Results  The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95% CI, 2.3 to 2.6); moisturizer, 2.5 (95% CI, 2.3 to 2.6); placebo, 2.5 (95% CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol, −1.4 (95% CI, −1.6 to −1.2); moisturizer, −1.2 (95% CI, −1.4 to −1.0); and placebo, −1.3 (95% CI, −1.5 to −1.1). No significant differences were seen between estradiol (P = .25) or moisturizer (P = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95% CI, 4.0 to 6.9) and placebo (4.5; 95% CI, 2.8 to 6.1) (P = .64), and between moisturizer (3.1; 95% CI, 1.7 to 4.5) and placebo (P = .17).

Conclusions and Relevance  Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.

Trial Registration  clinicaltrials.gov Identifier: NCT02516202

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