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Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck.
SYNOPSIS: In this 12-week randomized, controlled trial of 302 women, neither vaginal estrogen nor vaginal moisturizer was more effective than placebo for reducing the participants’ most bothersome symptom (pain with vaginal penetration, vulvovaginal itching, vulvovaginal pain, vaginal dryness, or vulvovaginal irritation).
SOURCE: Mitchell CM, Reed SD, Diem S, et al. Efficacy of vaginal estradiol or vaginal moisturizer vs. placebo for treating postmenopausal vulvovaginal symptoms: A randomized controlled trial. JAMA Intern Med 2018; March 19. doi: 10.1001/jamainternmed.2018.0116.
This was a randomized, double-blind, placebo-controlled, 12-week trial to assess treatments for genitourinary syndrome of menopause (GSM). Inclusion criteria were women age 45 to 70 years who were at least two years since last menses with at least one moderate to severe symptom of vulvovaginal itching, pain, irritation, or dryness experienced at least weekly in the past 30 days or pain with vaginal penetration at least once monthly. Exclusion criteria were current vaginal infection, use of hormonal medication in the past two months, use of antibiotics or vaginal moisturizer in the past month, or chronic premenopausal vulvovaginal symptoms. Women were randomized 1:1:1 to Vagifem 10 mcg tablet + placebo vaginal gel, placebo vaginal tablet + over-the-counter Replens vaginal moisturizer, or placebo tablet + placebo gel. Vaginal tablets were to be used daily for two weeks and then twice a week for the remaining 10 weeks and the vaginal moisturizer/placebo gel was used every three days throughout the trial. The placebo gel was similar to KY Jelly. The primary outcome was the severity of the most bothersome symptom (MBS) defined by the subject at enrollment (vulvovaginal itching, pain, irritation, dryness, or pain with vaginal penetration) rated from 0 to 3 (none, mild, moderate, severe). Secondary outcomes included the vaginal symptom index (mean severity score of the five vulvovaginal symptoms listed as MBS choices), Female Sexual Function Index, vaginal maturation index, and vaginal pH. Outcomes were assessed at four and 12 weeks.
A total of 302 women were randomized and only 3% were lost to follow-up. The mean age of the sample was 61 years and the majority were white (≥ 85%), married (≥ 81%), and sexually active (67% male partner, 1% female partners, 32% self-stimulation only). Participants reported the following MBS: pain with vaginal penetration (60%), vaginal dryness (21%), itching (7%), irritation (6%), and pain (5%). Vaginal estradiol tablet + placebo gel compared to placebo tablet + placebo gel reduced MBS severity by similar degrees (-1.4 vs. -1.3; P = 0.25). Vaginal moisturizer + placebo tablet compared to dual placebo also reduced MBS severity by similar amounts (-1.2 vs. -1.3; P = 0.31). Vaginal estradiol showed expected improvements in vaginal pH and increased the vaginal maturation index compared to placebo (46% vs. 12%; P < 0.001 and 57% vs. 11%; P < 0.001, respectively). The vaginal moisturizer did not affect these indices. There was no difference between the three groups on the Female Sexual Function Index. Although treatment satisfaction was similar between the three groups, more women in the estradiol tablet arm reported a “meaningful benefit” from treatment than the placebo group (80% vs. 65%; P = 0.02), but no difference was seen between the moisturizer and placebo groups (57% vs. 65%; P = 0.39).
Many postmenopausal women report symptoms related to vulvovaginal atrophy such as vaginal dryness (70%) and dyspareunia (40%).1 With the decline of estrogen in the menopausal period, the vulvovaginal tissue becomes thinner, the vagina becomes more alkaline, and vaginal secretions can decrease.2 The North American Menopause Society (NAMS) has termed this the GSM. Treatment recommendations include vaginal lubricants, vaginal moisturizers, and local vaginal estrogen if systemic estrogen therapy is not needed or desired. Vaginal moisturizers are supposed to have components that adhere to the vagina, allowing intermittent dosing, whereas vaginal lubricants typically are used prior to intercourse. Vaginal estrogen treatments include 10 mcg estradiol tablets, a three-month estradiol vaginal ring that releases 7.5 mcg daily, and estradiol or conjugated estrogen cream.2
The authors of this study decided to evaluate the efficacy of vaginal estradiol tablets and vaginal moisturizer, comparing each to a placebo. They felt that many women avoided products containing estrogen because of concerns about safety, so they wanted to assess a low-dose estrogen product and a moisturizer product. The results were surprising given that vaginal estradiol tablets did no better than placebo or vaginal moisturizer (although it was not technically a head-to-head trial) in terms of participant symptoms. Vaginal estradiol tablets were more effective in improving objective markers of vaginal health showing their biologic action. A previous Cochrane Review concluded that vaginal estrogen in various forms was superior to placebo, although the quality of the evidence was low, mostly because of small sample sizes.3 In addition, a recent systematic review of the evidence by the Society of Gynecologic Surgeons also concluded that “all commercially available vaginal estrogens effectively relieve common vulvovaginal atrophy-related complaints.”4 The fact that the vaginal moisturizer did no better than placebo gel is not as surprising, since the placebo gel was similar to KY Jelly, containing hydroxyethylcellulose and having a similar viscosity.
An accompanying editorial by two internists concluded that women should just choose the cheapest over-the-counter lubricant available to treat vulvovaginal symptoms rather than visiting their physician for a vaginal estrogen prescription.5 This conclusion seems extreme as there certainly are limitations to this study. The follow-up was short-term (12 weeks) and the use of the placebo gel likely contributed to the large placebo response. In addition, 10 mcg of estradiol may be too low of a dose to treat dyspareunia and other bothersome symptoms in some women. The response of NAMS to this study was to state that a “single short-term and underpowered clinical trial does not override a large body of previous evidence.”6 I agree with that statement and likely will not change my practice based on this study. NAMS already currently recommends vaginal lubricants and moisturizers as first-line treatment for GSM. If a woman fails those treatments, then a trial of vaginal estrogen makes clinical and biologic sense.
Financial Disclosure: OB/GYN Clinical Alert’s Editor, Jeffrey T. Jensen, MD, MPH, reports that he is a consultant for and receives grant/ research support from Bayer, Merck, ContraMed, and FHI360; he receives grant/research support from Abbvie, HRA Pharma, Medicines 360, and Conrad; and he is a consultant for the Population Council. Peer Reviewer Catherine Leclair, MD; Nurse Planners Marci Messerle Forbes, RN, FNP, and Andrea O’Donnell, FNP; Editorial Group Manager Terrey L. Hatcher; Executive Editor Leslie Coplin; and Editor Journey Roberts report no financial relationships relevant to this field of study.