Endometrial Safety of Low-dose Vaginal Estrogens in Menopausal Women

A Systematic Evidence Review

Ginger D. Constantine, MD; Shelli Graham, PhD; Kate Lapane, PhD; Kathleen Ohleth, PhD; Brian Bernick, MD; James Liu, MD; Sebastian Mirkin, MD


Menopause. 2019;26(7):800-807. 

In This Article

Abstract and Introduction


Objective: The aim of the study was to systematically review studies that evaluated endometrial hyperplasia or cancer incidence with unopposed vaginal estrogens.

Methods: PubMed and EMBASE were searched from inception to August 2017 for relevant articles and abstracts. Bibliographies of review articles and abstracts of major women's health medical meetings were examined. Eligible studies (independently reviewed by 4 authors) had to report menopausal vaginal estrogen use and endometrial histology, or incidence of endometrial hyperplasia or cancer.

Results: Of 5,593 abstracts from the literature search and 47 articles from other sources, 36 articles and 2 abstracts were eligible, describing 20 randomized controlled studies, 8 interventional studies, and 10 observational studies. Collectively, the studies did not support an increased risk of endometrial hyperplasia or cancer with low-dose vaginal estrogens. Rates of endometrial cancer and hyperplasia were 0.03% and 0.4%, respectively, from 20 randomized controlled trials (2,983 women) of vaginal estrogens. Overall, reports of endometrial hyperplasia were observed with various doses and durations and appeared sporadic (except 1.25 mg conjugated equine estrogens), consistent with endometrial hyperplasia rates in the general population. A Denmark registry study was an exception and may be of limited applicability to the United States. The Women's Health Initiative Observational Study showed no association (1.3 cases/1,000 women-years with vaginal estrogens versus 1.0/1,000 women-years for nonuse).

Conclusion: This systematic review supports the use of low-dose vaginal estrogens for treating vulvar and vaginal atrophy in menopausal women without a concomitant progestogen. This review does not support increased endometrial hyperplasia or cancer risk with low-dose, unopposed vaginal estrogens; however, longer-term, real-world data are needed.


More than two million women in the United States are estimated to use vaginal estrogen products to treat symptomatic vulvar and vaginal atrophy.[1–3] Because most women do not use vaginal estrogens with concomitant progestogen, examination of the impact of unopposed vaginal estrogens on the endometrium is an important safety parameter. Although it may be well accepted that local unopposed vaginal estrogens do not have the same stimulatory effects on the endometrium as unopposed oral estrogens, a lesser association between vaginal estrogen use and endometrial hyperplasia or cancer has not been systemically reviewed in published studies. A systematic review of the published clinical evidence to examine the endometrial safety of vaginal estrogens would enhance future development of novel, safe, and effective, low-dose vaginal estrogen products. The objective of this systematic review was to assess the endometrial safety of low-dose vaginal estrogens in menopausal women in the published medical literature.