Prevention of Menopause-Related Ovarian Epithelial Cancer

描述(由申请人提供)： 卵巢癌是北美女性死于妇科恶性肿瘤的主要原因，在女性中排名第五。大多数(约70%)卵巢癌是在癌症扩散到卵巢外并扩散到腹部腹膜时被诊断出来的，大多数(约85%)是在绝经后的女性中诊断出来的。如果发现仍局限于卵巢，治疗成功率很高，5年存活率超过90%。然而，目前的检测方法不可靠或很差，可行的预防策略势在必行。上皮性卵巢癌的风险与生育史有很好的联系，不间断排卵频率和不产仔增加了风险，产次和口服避孕药的使用明显降低了风险。流行病学证据表明，孕酮是减少排卵并提供独立的风险降低的关键因素，孕酮在妊娠和口服避孕药中都会升高。黄体酮的效果可能会因使用时间和持续时间的不同而不同，也可能在绝经前和绝经后的妇女之间有所不同。一些研究表明，激素相关风险因素对绝经前卵巢癌的保护作用可能比绝经后卵巢癌更大。这是一个重要的问题，因为女性可以预期在她们的生育年龄过后能活三分之一或更多的时间。在这项研究中，我们将使用生殖细胞缺陷的WV小鼠模型来检测孕酮预防或降低卵巢癌风险的能力。这些小鼠模仿更年期生物学，并发展出类似于人类卵巢癌前病变的上皮病变。当在卵巢癌中经常缺失的细胞周期蛋白依赖性激酶抑制因子p27kip1基因的缺失加上Wv/Wv基因的缺失时，卵巢肿瘤就会发展为恶性特征，并更接近于人类卵巢肿瘤。我们的假设是，绝经后发生的卵巢卵泡枯竭是卵巢癌风险的基础，卵泡储备和绝经状态可能会改变黄体酮预防卵巢癌的能力，因此在绝经前服用黄体酮可能是最有效的。我们将在卵泡耗尽之前(绝经前)(目标1)和(绝经后)卵泡耗尽(目标2)之前给WV雌性小鼠注射黄体酮，以确定对卵巢功能、血清激素水平和肿瘤发展的影响(目标3)。其目标是为绝经后妇女的卵巢癌制定合理的预防策略。

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.