Do Vaginal Estrogens Increase Endometrial Proliferation Risk?

to the editor: I am concerned about a discrepancy in this article on the risk of endometrial proliferation with use of vaginal estrogens. In the Vulvovaginal Symptoms section, it says: “Physicians should reassure patients that vaginal estrogen does not cause endometrial proliferation and that adding a progestogen for endometrial protection is not necessary.” However, the next paragraph states: “Vaginal administration of estradiol may cause an increase in serum estradiol levels in some patients, but data are lacking about the long-term risks of breast cancer, [venous thromboembolism], or endometrial proliferation for patients who use low-dose vaginal estrogen therapy.”

I would like clarification about whether data on the risks of endometrial proliferation with vaginal estrogen use are unclear or not.

in reply: Dr. Andreini asks about the risk of endometrial proliferation with use of vaginal (topical) estrogen therapy for vulvovaginal symptoms. Patients using recommended doses of intravaginal estrogen to treat vulvovaginal atrophy have a very low risk of endometrial proliferation or hyperplasia. Numerous studies have compared the effectiveness and safety of various local estrogen formulations, including effects on the endometrium. However, it can be hard to evaluate these studies. Some use endometrial biopsy results, a robust indicator of proliferation or hyperplasia, whereas others use arguably less definitive indicators, such as bleeding after progestogen challenge testing or endometrial thickness measured by transvaginal sonography.

Data are available that used endometrial biopsy to assess the safety of local estrogen therapy. A Cochrane review of 19 trials found a nonsignificant 2 percent incidence of simple hyperplasia (vaginal ring versus cream) and a 4 percent incidence of hyperplasia (one simple, one complex) when conjugated equine estrogen cream (Premarin) was compared with an estradiol tablet.¹ Recent year-long studies of vaginal conjugated estrogen cream (423 patients) and low-dose estradiol vaginal tablets (292 patients) revealed no cases of endometrial hyperplasia or cancer as determined by endometrial biopsy.^2,3 These reassuring data have led several organizations to state that patients using only local estrogen do not need cotherapy with progestogens for endometrial protection.^4,5 However, as stated in our review, it is unknown if endometrial proliferation, hyperplasia, or malignancy can occur after long-term treatment (many years) with local estrogen.

Patients considering local estrogen therapy should be told that short-term data are reassuring that endometrial proliferation, hyperplasia, or malignancy appears to be rare (and nonexistent in several newer studies), but we recommend that they return for evaluation if unexpected vaginal bleeding occurs. We thank Dr. Andreini for the interest in our review.