Prevention of Menopause-Related Ovarian Epithelial Cancer

预防更年期相关的卵巢上皮癌

• 批准号: 7874452
• 负责人: ELIZABETH R SMITH
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874452
• 关键词: Abdomen; Age; Anovulation; Aspirin; Benign; Biology; Cause of Death; Cyclin-Dependent Kinase Inhibitor; Cyclooxygenase Inhibitors; Detection; Development; Diagnosis; Epidemiology; Epithelial; Epithelial ovarian cancer; Estrogens; Female; Frequencies; Genes; Genotype; Germ Cells; Goals; Gonadotropins; Gynecologic; Histology; Hormonal; Hormones; Human; Lesion; Life; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Menopause; Methods; Modeling; Mus; North America; Oral Contraceptives; Ovarian; Ovarian Follicle; Ovary; Ovulation; Ovulation Inhibition; Peritoneal; Phenotype; Postmenopause; Pregnancy; Premenopause; Preneoplastic Change; Prevention; Prevention strategy; Preventive; Progesterone; Reproductive History; Risk; Risk Factors; Risk Reduction; Serum; Staging; Survival Rate; Testing; Time; Tissues; Woman; base; cancer diagnosis; cancer risk; mouse model; ovarian neoplasm; parity; prevent; protective effect; reproductive; reproductive hormone; research study; success; tumor

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.

描述（由申请人提供）： 卵巢癌是北美女性妇科恶性肿瘤死亡的主要原因，也是女性中第五大最常见的癌症。大多数（约70%）卵巢癌是在癌症扩散到卵巢外时诊断出来的，已经扩散到腹部的腹膜内层，大多数（约85%）是在绝经后的妇女中诊断出来的。如果在卵巢中发现，治疗的成功率很高，5年生存率超过90%。然而，目前的检测方法是不可靠的或差的，可行的预防战略是必要的。上皮性卵巢癌的风险与生育史密切相关，其中不间断的排卵频率和非产次增加了风险，而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，孕激素，这是由怀孕和口服避孕药升高，是关键的代理，采取行动，以减少排卵，并提供一个独立的风险降低。孕酮的效果可能会有所不同，这取决于使用的时间和持续时间，以及绝经前和绝经后妇女之间。一些研究表明，与绝经相关的风险因素可能对绝经前卵巢癌比绝经后卵巢癌提供更大的保护作用。这是一个重要的问题，因为妇女在生育年龄之后可以预期寿命超过三分之一或更多。在这项研究中，我们将使用生殖细胞缺陷的Wv小鼠模型来检查孕酮预防或降低卵巢癌风险的能力。小鼠模仿更年期生物学，并发展类似于人类卵巢肿瘤前变化的上皮病变。当周期蛋白依赖性激酶抑制剂p27 kip 1基因（其表达在卵巢癌中经常丢失）的缺失被添加到Wv/Wv基因型中时，卵巢肿瘤发展出恶性特征，并且更接近于人类卵巢肿瘤。我们的假设是，绝经期发生的卵泡耗竭是卵巢癌风险的基础，卵泡储备和绝经状态可能会改变孕酮预防卵巢癌的能力，因此在绝经前给予孕酮可能最有效。我们将在卵泡耗竭之前（绝经前）（目标1）和卵泡耗竭之后（绝经后）（目标2）对Wv雌性小鼠给予孕酮，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）。目的是为绝经后妇女卵巢癌制定合理的预防策略。