Long-Term Use of Phytoestrogens and the Endometrium

Abstract & Commentary

Synopsis: Long-term treatment (up to 5 years) with soy phytoestrogens was associated with an increased occurrence of endometrial hyperplasia. These findings call into question the long-term safety of phytoestrogens with regard to the endometrium.

Source: Unfer V, et al. Fertil Steril. 2004;82:145-148.

Unfer and colleagues from italy conducted a randomized, double-blind, placebo-controlled study of soy phytoestrogens that lasted 5 years. Two hundred nintey-eight (298) women completed the trial, 179 women receiving daily soy tablets containing 150 mg isoflavones. Although no cases of malignancy were detected, after 5 years there were 5 cases of simple hyperplasia (3.2%) and 1 case of complex hyperplasia (0.6%) in the treated group compared with none in the placebo group.

Comment by Leon Speroff, MD

Phytoestrogens is a descriptive term applied to nonsteroidal compounds that have estrogenic activity or are metabolized into compounds with estrogenic activity. Phytoestrogens are classified into 3 groups: isoflavones, lignins, and coumestans. Soybeans contain isoflavones, the most common form of phytoestrogens (specifically genistein, daidzein, and a little glycitin). The average Japanese intake of isoflavones is about 50 mg per day. The rest of Asia has an average consumption of about 25-45 mg per day, and Western intake is less than 5 mg per day. The dose of isoflavones in this study is therefore relatively high, about twice the recommended dose (60 mg isoflavones) for a lipid response (a dose that is present in 25 g soy). Previous studies have concluded that isoflavones have no effect on the endometrium, but not a single study was longer than a year or two.

There is a case report of adenocarcinoma of the endometrium in a woman using phytoestrogens (Johnson E, et al. Obstet Gynecol. 2001;98:947-950). Is it possible that there is a risk of endometrial cancer associated with either high doses of phytoestrogens or long exposure to even standard or low doses or both? This 5-year trial suggests that it is appropriate to be concerned and questions the safety of low-dose estrogen exposure.

Estrogen normally promotes mitotic growth of the endometrium. Abnormal progression of growth through simple hyperplasia, complex hyperplasia, atypia, and early carcinoma has been associated with unopposed estrogen activity, administered either continuously or in cyclic fashion. Only 1 year of treatment with unopposed estrogen (0.625 mg conjugated estrogens or the equivalent) will produce a 20% incidence of hyperplasia, largely simple hyperplasia. In the 3-year PEPI trial, 30% of the women on unopposed estrogen developed adenomatous or atypical hyperplasia. Some 10% of women with complex hyperplasia progress to frank cancer, and complex hyperplasia is observed to antedate adenocarcinoma in 25-30% of cases. If atypia is present, 20-25% of cases will progress to carcinoma within a year.

Approximately 40 case-control and cohort studies have estimated that the risk of endometrial cancer in women on estrogen therapy (unopposed by a progestational agent) is increased by a factor of somewhere from 2 to 10 times the normal incidence of 1 per 1000 postmenopausal women per year. The risk increases with the dose of estrogen and with the duration of exposure (reaching a 10-fold increase with 10-15 years of use, perhaps an incidence of 1 in 10 with very long-term use), and lingers for up to 10 years after estrogen is discontinued. Although most endometrial cancer associated with estrogen use is of low grade and stage, and associated with better survival (probably because of early detection), the overall risk of invasive cancer and death is increased.

A short-term study (2 years) has indicated that one-half the usual standard dose of estrogen (in this case, 0.3 mg esterified estrogens) was not associated with an increased incidence of endometrial hyperplasia compared with a placebo group.1 However, we have learned that long-term exposure to low levels of estrogen can induce abnormal endometrial growth (it just takes longer), and, in my view, lower dose estrogen therapy requires either endometrial assessment annually or the addition of a progestin to the treatment regimen. This is supported by a case-control study from Washington that contained 18 cases and 9 controls who had exclusively used only 0.3 mg/d of unopposed conjugated estrogens.2 The use of this half-dose estrogen was associated with an overall 5-fold increased risk of endometrial cancer, reaching a relative risk of 9.2 in current users for more than 8 years’ duration. Although limited by small numbers, the conclusion is logical and consistent with our understanding of the importance of duration of exposure to any increased level of endometrial estrogen stimulation. In a randomized trial, endometrial hyperplasia was increased after 2 years of treatment with 0.3 mg conjugated estrogens without a progestin.3

The clinical principle appears to be the following: as the dose of daily estrogenic exposure decreases, the duration of exposure required to induce endometrial hyperplasia and cancer increases. This also raises concern regarding vaginal administration of very low doses of estrogen. The systemic absorption of estrogen from the low-dose estradiol ring or tablet is very low, especially after the vagina achieves estrogen-induced maturation (about 3 months). One would expect this low level of absorption to be free of the risk of endometrial hyperplasia; however, all studies have been too short (all 1 year or less, except one 2-year study) to determine long-term endometrial safety. Although systemic absorption occurs, the circulating estradiol levels with these low-dose methods remain in the normal postmenopausal range. Because the small increase in circulating estradiol levels causes distant target tissue responses (eg, an increase in bone density or an improvement in the lipid profile)4,5 clinicians cannot assure patients that these methods are totally free of systemic activity. Although the change in blood levels is very slight, and for that reason not effective for the relief of vasomotor symptoms, I believe long-term treatment requires ultrasonographic monitoring of endometrial thickness with biopsy when indicated. This ultrasonographic approach is more preferable than complicating the treatment regimen with the addition of a progestational agent. It makes sense for each patient to titrate her dose and schedule of treatment to balance an effective response with minimal dosing. For women who are breast cancer survivors and are considering this treatment, clinician and patient must accept a small, but real, unknown risk.

Long-term exposure to low doses of estrogen or to weak estrogenic substances (the phytoestrogens) may not be free of risk for endometrial hyperplasia and cancer, and, therefore, clinical concern and monitoring are indicated.


1. Notelovitz M, et al. Menopause. 1997;4:80-88.

2. Cushing KL, et al. Obstet Gynecol. 1998;91:35-39.

3. Pickar JH, et al. Fertil Steril. 2003;80:1234-1240.

4. Naessen T, et al. Am J Obstet Gynecol. 1997;177:115-119.

5. Naessen T, et al. J Clin Endocrinol Metab. 2001;86: 2757-2762.

Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, is Editor of OB/GYN Clinical Alert.