Background The role of estrogens in the pathogenesis of breast cancer has been well documented. This has led to the development of Anti-Estrogens (selective estrogens receptor modulators and Aromatase Inhibitors), used for treatment and prevention of breast cancer. These agents, however, have significant side effects, which are not acceptable to many healthy high-risk women. There is preliminary evidence that GSE acts as natural aromatase inhibitor1.

Commercial preparations of GSE are available as dietary supplements. Methods Plasma levels of estrone, estradiol, estrone-conjugates, testosterone and androstenedione will be measured prior to and 12 weeks after daily ingestion of GSE in 40 healthy postmenopausal women randomly assigned to one of four different doses.

Significance This study has the potential to quantify the effectiveness of a natural substance that mimics the action of pharmaceutical aromatase inhibitors. If we can prove that GSE decreases plasma estrogen levels we will conduct a larger study evaluating the use of GSE as a chemopreventive agent with mammographic breast density used as surrogate marker. The goal of this future study will be detection of a decrease in breast density in women taking GSE leading to large-scale recommendations of GSE to millions of healthy postmenopausal women to reduce their risk of breast cancer in a natural way.

Study Design/Overview This is a dose-finding pilot study. Plasma estrogen (E1, E2, E1-conjugates) and precursor androgen (testosterone and androstenedione) levels will be measured prior to and 12 weeks after daily ingestion of GSE in one of 4 (randomly assigned) doses in healthy postmenopausal women. Assuming a drop out rate of about 50% during the study, we plan to recruit 80 patients from the outpatient Regional Section of the Division of General Internal Medicine to yield a total of 40 subjects on whom the final hormonal measurements will be assayed.

Baseline visit

1. The study will be explained and informed consent will be obtained.
2. Body mass index will be recorded.
3. Patients will complete a breast cancer risk factor questionnaire and 2 menopausal symptom scales.

4. Patients will receive an appointment at the Charlton GCRC.

   1. Blood draws will be done at the GCRC. Blood will be drawn in sodium heparin tubes and processed using the GCRC. Plasma will be aliquotted into four 1.5 mL tubes per patient, frozen and stored at -70 C until all samples (including samples from the 12 week return visit) are ready for shipment to SFBC Taylor Technology, Incorporated; 107 College Road East, NJ for estrogen and androgen measurements.
   2. GSE, which will be stored at the GCRC pharmacy, will be handed out to the patients after randomization to one of four different dose groups of Grape Seed Extract (200 mg - 400 mg - 600 mg - 800 mg GSE/day). The GSE can be obtained at no cost from San Joaquin Valley Concentrate (SJVC) Fresno, California. (Note: if funding permits, we will purchase our supply from an independent marketer to remove the appearance of a conflict of interest caused by support from the manufacturer). Note: Our maximum dose of 800 mg/day (4 pills per day) is the equivalent of 11.4 mg/kg in a 70 kg woman. We do not believe women would be willing to take more than 4 GSE pills per day, so we have not proposed doses higher than 800 mg. It is unclear from the literature just what dose to propose. One study suggests a very high dose (70 capsules of 200 mg each) per day would be required to see a measurable effect. Other studies suggest doses much lower are necessary. Because of the uncertainty of the dose, we have included four dose levels and will ask women to take the GSE for 12 weeks to maximize the potential for a measurable effect. Weekly telephone calls Enrolled patients will be called once a week by the study coordinator to check for compliance and possible side effects.

Return visit at 12 weeks

1. Body mass index will be recorded.
2. Patients will complete 2 menopausal symptom scales.
3. Blood will be drawn in sodium heparin tubes and processed using the GCRC. Plasma will be aliquotted into four 1.5 mL tubes per patient, frozen and stored at -70 C until all samples from a total of 40 patients are ready for shipment to SFBC Taylor Technology, Incorporated; 107 College Road East, NJ for estrogen and androgen measurements.

Eligibility Criteria:

1. Postmenopausal (no menstrual period for 1 year or more)
2. Age 55 - 75 years
3. No personal cancer history (except for non-melanoma skin cancer)
4. No hormone replacement therapy or anti-estrogens within 6 months of baseline
5. Able to give informed consent

Exclusion Criteria

1. Known allergy to grapes or grape products
2. Currently on anticoagulants, antiplatelet agents, herbs (anticoagulant/antiplatelet properties), nonsteroidal anti-inflammatory agents, salicylates, thrombolytic agents.