Trial Information

Green Tea Extract: a Non-Surgical Alternative for Treatment of Uterine Fibroids

- Uterine leiomyoma (also known as fibroids) are benign estrogen-dependent tumors of the
uterine wall. Uterine fibroids are the most common tumors of the female reproductive
tract, occurring in 20-70% of premenopausal women in the reproductive age women and
cause multiple clinical complications such as acute and chronic pelvic pain as well as
excessive vaginal bleeding and iron deficiency anemia, moreover they are considered as
the leading indication for hysterectomy in reproductive age African American (AA)
women. The impact of these serious clinical complications on women's health is
tremendous. African American women are particularly affected as the prevalence of
uterine fibroids is about 4 times higher in that ethnic group compared to Caucasians.
Being a major health disparity issue, uterine fibroids appear to further diminish the
quality of life for AA women who also suffer from higher incidence of chronic diseases
such as diabetes, heart disease, obesity, and cancer. Currently there is no effective
long-term medicinal treatment for this common disease. GnRH analogues are effective
short medical therapy option. However, they are not approved for long-term (more than 3
months) because of the risk of irreversible bone loss and osteoporosis and other major
side effects. When these medications are discontinued, the fibroids return to their
original size with symptoms recurring, that is why they are FDA approved in uterine
fibroids only as preoperative adjuvant to improve the fibroid-related iron-deficiency
anemia. Surgery, usually in the form of hysterectomy, is the traditional treatment of
women with symptomatic uterine fibroids. Clearly hysterectomy is an effective treatment
but it precludes future fertility. This creates a major dilemma for women with
symptomatic uterine fibroids who have not completed their families or have not even
started a family. Problems with fibroids must be viewed as a public health concern as
well as a major health disparity issue. The general public in relation to this problem
must be concerned about the: (1) The decrease in the quality of life of women who are
affected, and hence the well-being of the whole family; (2) Interference with
inter-family dynamics and relationships. Decrease in productivity in the workforce/job
performance. Increase in cost of health care caused by the more than 600,000
hysterectomies/Y in USA alone.

- Green Tea Extract

This work will evaluate the utility of EGCG, green tea extract, which is a common
nutritional supplement, in symptomatic relief of this common women's health problem.
Considering the wide acceptability of nutritional supplements especially among African
American women, the ethnic group most affected by uterine fibroids, this project can
potentially provide an effective and inexpensive non-surgical alternative for management of
uterine fibroids. Green tea is a common agent used by women for multiple purposes.
Epigallocatechin gallate (EGCG) is the major catechin (about 80%) of green tea. EGCG exhibit
several useful biological effects including anti-inflammatory, anti-proliferative as well as
anti-oxidant effects. A study conducted by the United States Department of Agriculture
reported that green tea has potent anti-cancer effects against a wide range of human cancer
cells. Green tea's polyphenols, most notably EGCG, are considered responsible for those
positive effects. Green tea polyphenols have also been shown to inhibit key pathways of
tumor growth.

- Prior Human Experience with EGCG Several human clinical studies used EGCG for extended
periods of time in which EGCG was very well tolerated with virtually no reportable side
effects. Wolfarm and colleagues used oral EGCG 300 mg/day in cardiac patients and
reported improved endothelial function and increased brachial artery flow-mediated
dilation that paralleled changes in EGCG plasma concentration. reported on the
consumption of 500-1000 mg/day of oral EGCG for 3 months which resulted in marked
decrease in several anti-oxidative biomarkers compared to placebo. Numerous studies
have described favorable effects of EGCG when used in overweight and obese individuals
for extended durations. Chow et.al. reported on human use of EGCG with 30 healthy
volunteers randomly assigned to one of the following doses of Polyphenon E (a
decaffeinated green tea catechin mixture): 400, 800, or 1200 mg/day (10 subjects per
dose group). Only transient mild nausea was noted in 3% of the study participants and
was seen only at the highest study agent dose (1200 mg EGCG/day) and in the fasting
condition. Doses of 800mg were well tolerated with no reported side effects. Grapes
also contain polyphenols and catechins such as EGCG. EGCG is the most powerful of these
catechins that accounts for the favorable health effects from the use of grapes
extracts. Grapes polyphenols have been shown to inhibit key pathways of tumor growth.
Grapes EGCG appear to block each stage of tumor-genesis by modulating signaling
pathways involved in cell proliferation, transformation, inflammation, and oxidative
stress, which are clearly involved in pathogenesis of various tumors including uterine
fibroids. Freeze-dried table grapes powder has been used recently for several months in
pre-and post-menopausal women at doses of up to 36 gm/day. This dose corresponds to
about 800mg EGCG/day. This treatment was very well tolerated with no reported side
effects. This suggests that such supplement can be successfully administered to women
as part of life or diet modification programs.

- Preclinical Data Recent studies from our group demonstrated the ability of EGCG to
control the proliferation and to induce apoptosis in human leiomyomata cells in vitro
and in animal models. Our preclinical data in fibroid animal models demonstrates that
EGCG at a dose of 1.25mg/Kg/day added to drinking water was able to induce a highly
significant (up to 80%) shrinkage of fibroid lesions compared to untreated controls.
The treatment was well tolerated with no detected side effects. Such daily doses of
EGCG have been administered safely to human subjects in prior clinical trials. This
effect is partially attributed to potent inhibitory effect of EGCG on Catechol-O-methyl
transferase (COMT), an enzyme that we have recently linked to pathogenesis of uterine
fibroids. In this proposal we aim to evaluate the efficacy of Epigallocatechin gallate
(EGCG) in reducing the size of uterine fibroids and improving quality of life in women
with symptomatic uterine fibroids, as well as assess its safety profile.

- We have recently demonstrated elevated levels of expression of catechol-O-methyl
transferase (COMT) in uterine fibroids compared to adjacent normal myometrium, and
described its important role in fibroid pathogenesis.

- Interestingly, recent reports demonstrated that EGCG has potent anti-COMT activity.
These reports have shown that green tea extract intake is associated with weight loss
due to diet-induced thermo-genesis. This effect is generally attributed to EGCG. This
catechin is known to be capable of inhibiting COMT, which is the enzyme that degrades
nor-epinephrine, thus stimulating thermo-genesis. The inhibition of COMT by EGCG was
uncompetitive with respect to S-adenosylmethionine (SAM) suggesting that there is no
direct interaction between EGCG and the SAM-binding site on the COMT, yet there was
clear inhibition of COMT activity with increasing EGCG concentration. Additionally, the
Vmax values for methylation were decreased. Our preliminary data also showed that EGCG
inhibited COMT gene expression in a dose-dependent manner in human leiomyomata cells.

- Our hypothesis is that the use of the "EGCG" as a nutritional supplement will decrease
the size of uterine fibroids and improve fibroids-related clinical symptoms in women
resulting in a significant improvement in their quality of life.

- This work will evaluate the utility of a common nutritional supplement in symptomatic
relief of a very common women's health problem. Considering the availability, lower
cost, as well as the wide acceptability of nutritional supplements, this project can
potentially provide an inexpensive non-surgical alternative for management of uterine
fibroids which would have a major impact on health of women from all ethnic groups.