1. JAMA Intern Med. 2018 May 1;178(5):681-690. doi: 10.1001/jamainternmed.2018.0116.

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

Mitchell CM(1)(2), Reed SD(3), Diem S(4)(5), Larson JC(6), Newton KM(7), Ensrud
KE(4)(8), LaCroix AZ(9), Caan B(10), Guthrie KA(6).

Author information: 
(1)Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Boston.
(2)Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical
School, Boston, Massachusetts.
(3)Department of Obstetrics and Gynecology, University of Washington, Seattle.
(4)Department of Medicine, University of Minnesota, Minneapolis.
(5)Department of Epidemiology and Community Health, University of Minnesota,
(6)Fred Hutchinson Cancer Research Center, Seattle, Washington.
(7)Kaiser Permanente Washington Health Research Institute, Seattle.
(8)Department of Medicine, Minneapolis Veterans Affairs Health Care System,
Minneapolis, Minnesota.
(9)Department of Family Medicine and Public Health, University of California at
San Diego, La Jolla.
(10)Division of Research, Kaiser Permanente of Northern California, Oakland,

Comment in
    J Urol. 2019 Feb;201(2):232.

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.

DOI: 10.1001/jamainternmed.2018.0116 
PMCID: PMC5885275
PMID: 29554173