A double-blind randomized study on the effects of red clover isoflavones on the endometrium

Objective: To assess the effects of a red clover-derived isoflavone extract on the Ki-67 proliferative marker of endometrial biopsies in 45- to 50-yea r-old perimenopausal women. We hypothesized that we would be able to detect a decrease in the Ki-67 proliferative index during the late follicular pha se after a 3-month course of similar to 50 mg red clover isoflavones. Isofl avones have been found to have some antiestrogenic effects, and an antiprol iferative effect during the perimenopausal period may be especially useful owing to the excessive endometrial proliferation often characteristic of th is period. Design: In a double-blind, randomized, controlled study, 30 women between t he ages of 45 and 50 years consented to an endometrial biopsy before and af ter a 3-month course of either placebo or active isoflavone extract. The bi opsies were timed as close as possible to days 7-11 of the menstrual cycle, and simultaneous measurements of transvaginal endometrial thickness, uteri ne artery Doppler, hormone profiles, lipids, and bone markers were performe d. Results: Of 30 women, 2 did not return for a second biopsy, and a third had an unsuccessful second biopsy. Four subjects were excluded from the Intent ion to Treat analysis because they did not have a menstrual bleed within th e time frame of the study (3 subjects) or were tested on day 13 instead of between days 7 and 11 of the cycle (1 subject). There was no change in the Ki-67 proliferation index after treatment in either group. Eight subjects i n the placebo group and eight in the P-07 group had proliferative endometri al biopsies that were synchronized with estradiol levels at baseline and po st-treatment, and analysis of these subjects revealed no detectable change in the relationship between estradiol levels and Ki-67 with treatment in ei ther group. There was no change in fasting lipids, bone markers, uterine Do ppler resistance, or pulsatility index. Conclusion: In this small pilot study, we did not find, using immunohistoch emical quantification of the Ki-67 antigen, that red clover isoflavones had an antiproliferative effect in the endometrium. Small sample size, examina tion of a relatively short interval in the menstrual cycle, and isoflavone formulation may have contributed to our lack of findings; however, we belie ve that the issue of isoflavones and their possible antiproliferative effec t is deserving of further study. A simpler physiological model with less ho rmonal variability, such as healthy, recently menopausal women on predeterm ined doses of estrogen, may prove to be more informative.