Low-potency estrogen, such as 1 to 2 mg of estriol, is increasingly used in Europe in the belief that such formulations provide the benefits of hormone replacement therapy without the risk of endometrial hyperplasia and cancer. The risk of endometrial cancer with low-dose estrogen, however, has not been adequately studied. Weiderpass and colleagues investigated this risk in women 50 to 74 years of age who received hormone replacement therapy.
The population-based, case-control study was conducted in Sweden. A total of 789 cases of newly diagnosed endometrial cancer in postmenopausal women was identified through six regional cancer registries. These cases were matched by age to 3,368 women who served as the control group. Questionnaires were mailed to obtain data on the use of hormones and other pertinent information about the reproductive and medical history. Missing information was obtained by telephone interviews. The incidence of endometrial cancer in women who had used oral or vaginal low-potency estrogens was compared with that in women who reported never having used these compounds.
The use of oral estriol was reported by 20.1 percent of the patients with cancer compared with 10.8 percent of the control group. Women who had ever taken estriol had a twofold increased relative risk of endometrial cancer compared with the risk in those who had never taken oral estriol. Women exposed for less than five years had an odds ratio of 1.7 and those exposed for at least five years had an odds ratio of 3.0. Analysis of the duration of use revealed that the relative risk of endometrial cancer increased by 8 percent per year.
The association with oral estriol use was much stronger for well-differentiated (grade 1) cancer than for less-differentiated (grades 2 and 3) cancers. Vaginally administered estriol did not appear to be significantly related to the development of endometrial carcinoma.
The authors conclude that oral low-potency estrogen therapy (up to 2 mg of estriol daily) is associated with an increased risk of endometrial hyperplasia and cancer. They recommend that coadministration of progesterone be considered even when low-dose estrogen is used and that regular monitoring for pathologic changes of the endometrium be performed in patients receiving low-dose estrogen replacement therapy.