Prevention of Menopause-Related Ovarian Epithelial Cancer

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death from a gynecologic malignancy among women in North America and the fifth most frequently occurring cancer among women. Most (about 70%) ovarian cancers are diagnosed when the cancer has spread outside the ovary, having disseminated to the peritoneal lining of the abdomen, and most (about 85%) are diagnosed in women post-menopause. If detected while still localized in the ovary, the success rate of treatment is high, with a 5-year survival rate over 90%. However, current detection methods are unreliable or poor, and viable prevention strategies are imperative. The risk of epithelial ovarian cancer is well linked with reproductive history, where uninterrupted ovulation frequency and non-parity increase the risk, and parity and the use of oral contraceptives clearly reduce the risk. Epidemiological evidence suggests that progesterone, which is elevated by both pregnancy and oral contraceptives, is the critical agent, acting to reduce ovulation and provide an independent risk reduction. The effects of progesterone may differ depending upon timing and duration of use, and between pre- and post-menopausal women. Some studies suggest that hormone-related risk factors may provide a greater protective effect against pre-menopausal than post-menopausal ovarian cancers. This is an important question, since women can expect to live more one-third or more of their lives after their reproductive years. In this study we will examine the ability of progesterone to prevent or reduce ovarian cancer risk using the germ cell deficient Wv mouse model. The mice mimic menopausal biology and develop epithelial lesions that resemble preneoplastic changes in human ovaries. When deletion of the cyclin-dependent kinase inhibitor p27kip1 gene, whose expression is often lost in ovarian cancer, is added to the Wv/Wv genotype, the ovarian tumors develop malignant features and resemble more nearly human ovarian tumors. Our hypothesis is depletion of ovarian follicles that occurs with menopause underlies ovarian cancer risk, and that follicle reserve and menopause status may alter the ability of progesterone to prevent ovarian cancers, such that progesterone is likely most effective when given before menopause. We will administer progesterone to Wv female mice prior to follicle depletion (pre-menopause) (Aim 1) and after (post-menopause) follicle depletion (Aim 2) to determine the effects on ovarian function, serum hormone levels, and tumor development (Aim 3). The goal is to formulate rationale preventive strategies for ovarian cancer in post-menopausal women.