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的主要原因，也是女性中第五次最常见的癌症。当癌症扩散到卵巢以外，分布到腹部的腹膜外，大多数（约70％）的卵巢癌被诊断出来，大多数（约85％）在月经后诊断出。如果检测到仍在卵巢中的位置，则治疗的成功率很高，5年生存率超过90％。但是，当前的检测方法是不可靠的或差的，可行的预防策略必须进行。上皮卵巢癌的风险与生殖历史息息相关，在这些历史中，不间断的排卵频率和非准性增加了风险，平等和口服避孕药的使用明显降低了风险。流行病学证据表明，孕酮因妊娠和口服避孕药而升高，是关键的药物，致力于减少排卵并提供独立的风险降低。孕激素的作用可能取决于时间和使用时间，以及在绝经前和绝经后妇女之间的影响。一些研究表明，与青春期后的卵巢癌相比，与激素相关的危险因素可能为绝经前提供更大的保护作用。这是一个重要的问题，因为妇女可以期望在生殖时期过三分之一或更多的生活。在这项研究中，我们将使用缺乏生殖细胞的WV小鼠模型来检查孕酮预防或减少卵巢癌风险的能力。小鼠模仿了更年期生物学，并发展上皮病变，与人卵巢中的前塑性变化相似。当依赖细胞周期蛋白依赖性激酶抑制剂p27KIP1基因的缺失（其表达在卵巢癌中通常会丢失）被添加到WV/WV基因型中时，卵巢肿瘤会出现恶性特征，并且类似于几乎人类的卵巢肿瘤。我们的假设是对卵巢卵泡发生的耗竭，而更年期是卵巢癌风险的基础，而卵泡储备和更年期的状态可能会改变孕酮预防卵巢癌的能力，因此，在更年期之前给出时，孕酮可能是最有效的。我们将在卵泡耗竭之前对WV雌性小鼠进行孕激素（AIM 1）（AIM 1）和（春季后）卵泡耗竭后（AIM 2），以确定对卵巢功能，血清激素水平和肿瘤发展的影响（AIM 3）。目的是为绝经后妇女制定卵巢癌的预防策略。