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.