Abstract: We included 30 RCTs (6235 women) comparing different intra-vaginal oestrogenic preparations with each other and with placebo. The evidence was low to moderate quality; limitations were poor reporting of study methods and serious imprecision (effect estimates with wide confidence intervals) 1. Oestrogen ring versus other regimens Other regimens included oestrogen cream, oestrogen tablets and placebo. There was no evidence of a difference in improvement in symptoms (participant assessment) either between oestrogen ring and oestrogen cream (odds ratio (OR) 1.33, 95% CI 0.80 to 2.19, two RCTs, n = 341, I2 = 0%, low-quality evidence) or between oestrogen ring and oestrogen tablets (OR 0.78, 95% CI 0.53 to 1.15, three RCTs, n = 567, I2 = 0%, low-quality evidence). However, a higher proportion of women reported improvement in symptoms following treatment with oestrogen ring compared with placebo (OR 12.67, 95% CI 3.23 to 49.66, one RCT, n = 67). With respect to endometrial thickness, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring (OR 0.36, 95% CI 0.14 to 0.94, two RCTs, n = 273; I2 = 0%, low-quality evidence). This may have been due to the higher doses of cream used. 2. Oestrogen tablets versus other regimens Other regimens in this comparison included oestrogen cream, and placebo. There was no evidence of a difference in the proportions of women who reported improvement in symptoms between oestrogen tablets and oestrogen cream (OR 1.06, 95% CI 0.55 to 2.01, two RCTs, n = 208, I2 = 0% low-quality evidence). A higher proportion of women who were treated with oestrogen tablets reported improvement in symptoms compared to those who received placebo using a fixed-effect model (OR 12.47, 95% CI 9.81 to 15.84, two RCTs, n = 1638, I2 = 83%, low-quality evidence); however, using a random-effect model did not demonstrate any evidence of a difference in the proportions of women who reported improvement between the two treatment groups (OR 5.80, 95% CI 0.88 to 38.29). There was no evidence of a difference in the proportions of women with increase in endometrial thickness between oestrogen tablets and oestrogen cream (OR 0.31, 95% CI 0.06 to 1.60, two RCTs, n = 151, I2 = 0%, low-quality evidence). 3. Oestrogen cream versus other regimens Other regimens identified in this comparison included isoflavone gel and placebo. There was no evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and isoflavone gel (OR 2.08, 95% CI 0.08 to 53.76, one RCT, n = 50, low-quality evidence). However, there was evidence of a difference in the proportions of women with improvement in symptoms between oestrogen cream and placebo with more women who received oestrogen cream reporting improvement in symptoms compared to those who were treated with placebo (OR 4.10, 95% CI 1.88 to 8.93, two RCTs, n = 198, I2 = 50%, low-quality evidence). None of the included studies in this comparison reported data on endometrial thickness. There was no evidence of a difference in efficacy between the various intravaginal oestrogenic preparations when compared with each other. However, there was low-quality evidence that intra-vaginal oestrogenic preparations improve the symptoms of vaginal atrophy in postmenopausal women when compared to placebo. There was low-quality evidence that oestrogen cream may be associated with an increase in endometrial thickness compared to oestrogen ring; this may have been due to the higher doses of cream used. However there was no evidence of a difference in the overall body of evidence in adverse events between the various oestrogenic preparations compared with each other or with placebo.

Plain-language summary: We found 30 randomised controlled trials comparing intravaginal oestrogenic preparations with one another or with placebo in a total of 6235 postmenopausal women undergoing treatment for the symptoms of vaginal atrophy. The evidence is current to April 2016. There was no evidence of a difference in the proportions of women who reported improvement in symptoms of vaginal atrophy between the following treatment comparisons: oestrogen ring and oestrogen cream, oestrogen ring and oestrogen tablets, oestrogen tablets and oestrogen cream, oestrogen cream and isoflavone gel. However, a higher proportion of women reported improvement in symptoms in the following active treatments compared with placebo: oestrogen ring versus placebo, oestrogen tablets versus placebo and oestrogen cream versus placebo. In the case of oestrogen tablets versus placebo and using a random-effect model for analysis of the data because of substantial heterogeneity, there was no longer evidence of a difference in effect on improvement in symptoms. With respect to safety, a higher proportion of women who received oestrogen cream showed evidence of increase in endometrial thickness compared to those who were treated with oestrogen ring, which may have been due to the higher doses of cream used. However, there was no evidence of a difference in the proportions of women with increase in thickness of the lining of the womb between oestrogen tablets and oestrogen cream. The evidence was of low quality for both improvement in symptoms as reported by women and increase in endometrial thickness. The main limitations of the evidence were poor reporting of study methods, and lack of precision (i.e. effect estimates with wide confidence intervals) in the findings for both outcomes.